Imidazopyridine and imidazopyrimidine antiviral agents

ABSTRACT

The present invention concerns antiviral compounds, their methods of preparation and their compositions, and use in the treatment of viral infections. More particularly, the invention provides imidazopyridine and imidazopyrimidine derivatives (Formula I) for the treatment of respiratory syncytial virus infection.

This application claims the benefit of U.S. Provisional Application Nos.60/263,363 filed Jan. 22, 2001 and 60/211,447 filed Jun. 13, 2000,respectively.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention concerns antiviral compounds, their methods ofpreparation and their compositions, and use in the treatment of viralinfections. More particularly, the invention provides imidazopyridineand imidazopyrimidine derivatives (Formula I) for the treatment ofrespiratory syncytial virus infection.

2. Background Art

Respiratory syncytial virus (RSV) is the leading cause of serious lowerrespiratory tract infection in infants, children, elderly andimmunocompromised persons. Severe infection of the virus may result inbronchiolitis or pneumonia which may require hospitalization or resultin death. (JAMA, 1997, 277, 12). Currently only Ribavirin is approvedfor the treatment of this viral infection. Ribavirin is a nucleosideanalogue which is administered intranasally as an aerosol. The agent isquite toxic, and its efficacy has remained controversial. Other thanRibavirin, RespiGam and Synagis are an immunoglobulin and monoclonalantibody, respectively, that neutralize RSV. They are the only twobiologics that have been approved for prophylactic use in high riskpediatric patients for RSV infection. Both RespiGam and Synagis are veryexpensive and require parental administration.

Many agents are known to inhibit respiratory syncytial virus (De Clercq,Int. J. Antiviral Agents, 1996, 7, 193). Y. Tao et al. (EP 0 058 146 A1,1998) disclosed that Cetirizine, a known antihistamine, exhibitedanti-RSV activity. Tidwell et al., J. Med. Chem. 1983, 26, 294 (U.S.Pat. No. 4,324,794, 1982), and Dubovi et al., Antimicrobial Agents andChemotherapy, 1981, 19, 649, reported a series of amidino compounds withthe formula shown below as inhibitors of RSV.

Hsu et al., U.S. Pat. No. 5,256,668 (1993) also disclosed a series of6-aminopyrimidones that possess anti-viral activity against RSV.

In addition, Y. Gluzman, et al., (AU Patent, Au-A-14,704, 1997) and P.R. Wyde et al. (Antiviral Res. 1998, 38, 31) disclosed a series oftriazine containing compounds that were useful for the treatment and/orprevention of RSV infection.

Another series of compounds structurally related to this invention arepyrido[1,2-a]benzoazoles and pyrimidio[1,2a]benzimidazoles disclosed byS. Shigeta et al in Antiviral Chem. & Chemother. 1992, 3, 171. Thesecompounds have demonstrated inhibition of orthomyxovirus andparamyxovirus replication in HeLa cells. The structures of thesecompounds are shown in formulas Id and Ie, in which F═NH, S, or O;Q═—NHCOPh, —COOH, COOEt, or CN; T═COMe, CN, or COOEt; G═O or NH.

A bis-benzimidazole with an ethylenediol linker shown below has alsobeen reported as a potent inhibitor of rhinoviruses (Roderick, et al. J.Med. Chem. 1972, 15, 655).

Other structurally related compounds are bis-benzimidazoles whichpossess antifungal activity (B. Cakir, et al. Eczacilik Fak. Derg. 1988,5, 71).

Most recently Yu et al. have discovered a series of benzimidazoles(Formula II) for the treatment and prevention of RSV infection (WO00/04900). In addition, Theodore Nitz has also found a series ofcompounds with Formula III that inhibit RSV in Hep-2 cell tissue cultureassay (WO 99/38508). Although many other agents are known to inhibitrespiratory syncytial virus (De Clercq, Int. J. Antiviral Agents, 1996,7, 193) none of them have been used in human clinical trials. Thus,there is a medical need for a convenient and less expensive anti-viralagent for the treatment and prevention of RSV infection.

SUMMARY OF THE INVENTION

This invention relates to compounds having the Formula I, andpharmaceutically acceptable salts thereof

wherein:

W is O or S;

R₁ is —(CR′R″)_(n)—X;

X is H, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl being optionally substituted with one to six of the same ordifferent halogen atoms; halogen, CN, OR′, OCOR″″, NR′R″, NR′COR″,NR′CONR″R′″, NR′SO₂R″, NR′COOR″, COR′, CR′″NNR′R″, CR′NOR″, COOR′,CONR′R″, SO_(m)R′, PO(OR′)₂, aryl, heteroaryl or non-aromaticheterocycle;

m is 0-2; n is 2-6;

R₂ is

(i) H, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, —(CH₂)_(t), C₃₋₇ cycloalkyl, —(CH₂)_(t), C₄₋₇cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl being optionally substituted with one to six of the same ordifferent halogen atoms; SO₂R″, SO₂NR′R″ or CN; wherein t is 1-6;

(ii) —(CR′R″)_(n′)—Y, wherein Y is CN, OR′, OCONR′R″, NR′R″, NCOR′,NR′SO₂R″, NR′COOR″, NR′CONR″R′″, COR′, CR′″NNR′R″, CR′NOR″, COOR′,CONR′R″, SO_(m)R′, SO₂NR′R″ or PO(OR′)₂; wherein

m is 0-2 and n′ is 1-6;

(iii) —(CR′R″)_(n″)—C₆H₄—Z, wherein the Z group may be in the ortho,meta or para position relative to the —(CH₂)_(n″) group; Z is CN, OR′,OCONR′R″, NO₂, NR′R″, NCOR′, NR′SO₂R″, NR′COOR″, NR′CONR″R′″, COR′,CR′″NNR′R″, CR′NOR″, COOR′, CONR′R″, SO_(m)R′, SO₂NR′R″ or PO(OR′)₂;

m is 0-2; n″ is 0-6; or

(iv) —(CR′R″)n′″-heteroaryl, wherein n′″ is 0-6;

(v) —(CR′R″)n′″-non-aromatic heterocycle, wherein n′″ is 0-6;

R₃, R₄, R₅ and R₆ are each independently hydrogen, halogen, C₁ ₆ alkyl,C₁₋₆ alkyl substituted with one to six of the same or different halogenatoms, OR′, CN, COR′, COOR′, CONR′R″, or NO₂;

A, B, E, D are each independently C—H, C—Q—, N, or N—O; provided atleast one of A, B, E or D is not C—H or C—Q; wherein Q is halogen, C₁₋₃alkyl or C₁₋₃ alkyl substituted with one to three of the same ordifferent halogen atoms; and

R′, R″, R′″ are each independently H, C₁₋₆ alkyl, C₂ ₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, each of said alkyl,alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionallysubstituted with one to six of the same or different halogen atoms; orR′ and R″ taken together form a cyclic alkyl group having 3 to 7 carbonatoms; benzyl or aryl;

R″″ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, NR′R″, CR′NR″R′″, aryl, heteroaryl, non-aromaticheterocycle; and

Non-aromatic heterocycle is a 3-7 membered non-aromatic ring containingat least one and up to 4 non-carbon atoms selected from the groupconsisting of O, S, N, and NR′;

Aryl is phenyl, naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl;

Heteroaryl is a 4-7 membered aromatic ring which contains one to fiveheteroatoms independently selected from the group consisting of O, S, Nor NR′, wherein said aromatic ring is optionally fused to group B′;

B′ is an aromatic group selected from the group consisting of phenyl,1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl;

Aryl, B′, said 4-7 membered aromatic ring, and said 3-7 memberednon-aromatic ring may each independently contain one to fivesubstituents which are each independently selected from R₇, R₈, R₉, R₁₀or R₁₁; and R₇, R₈, R₉, R₁₀ and R₁₁ are each independently

(i) H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl being optionally substituted with one to six of the same ordifferent halogen atoms; and

(ii) halogen, CN, NO₂, OR′, NR′R″, COR′, COOR′, CONR′R″, OCOR′, NR′COR″,SO_(m)R′, SO₂NR′R″, PO(OR′)₂.

A preferred embodiment includes compounds of Formula I whereinheteroaryl is selected from the group consisting of 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazol-5-one,1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl,1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, tetrazole and phenoxazinyl.

Another preferred embodiment includes compounds of Formula I wherein:

R₁ is —(CH₂)_(n)—X;

X is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl being optionally substituted with one to six of the same ordifferent halogen atoms; halogen, CN, OR′, OCOR″″, NR′R″, NR′COR″,NR′COOR″, COR′, CR′″NNR′R″, CR′NOR″, COOR′, CONR′R″, SO_(m)R′, aryl orheteroaryl;

m is 0-2; n is 2-4;

R₂ is

(i) H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, —(CH₂)_(t) C₃₋₇ cycloalkyl, —(CH₂)_(t) C₄₋₇ cycloalkenyl,each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl beingoptionally substituted with one to six of the same or different halogenatoms; SO₂R″, SO₂NR′R″ or CN; wherein t is 1-6;

(ii) —(CH₂)_(n′)—Y, wherein Y is CN, OR′, COR′, COOR′, CONR′R″,SO_(m)R′, SO₂NR′R″, PO(OR′)₂ wherein m is 0-2 and n′ is 1-6; or

(iii) —(CH₂)n″—C₆H₄—Z, wherein the Z group may be in the ortho, meta orpara position relative to the —(CH₂)n″ group; Z is CN, OR′, COR′ orSO_(m)R′; m is 0-2; n″ is 0-3;

R₃, R₄, R₅, and R₆ are each independently hydrogen, halogen, C₁₋₆ alkyl,optionally substituted with one to six of the same or different halogenatoms; and

A, B, E, D are each independently C—H or N; provided at least one of A,B, E or D is not C—H.

Another preferred embodiment includes compounds of Formula I wherein:

R₃, R4, R₅ and R₆ are each H;

A, B and D are each C—H; and

E is N.

Another preferred embodiment includes compounds of Formula I wherein:

R₃, R₄, R₅ and R₆ are each H;

A, B and E are each C—H; and

D is N.

In another embodiment of the invention there is provided a method fortreating mammals infected with RSV, and in need thereof, which comprisesadministering to said mammal a therapeutically effective amount of oneor more of the aforementioned compounds of having Formula I, includingpharmaceutically acceptable salts thereof.

Another embodiment includes a pharmaceutical composition which comprisesa therapeutically effective amount of one or more of the aforementionedanti-RSV compounds having Formula I, including pharmaceuticallyacceptable salts thereof, and a pharmaceutically acceptable carrier.

The term pharmaceutically acceptable salt includes solvates, hydrates,acid addition salts and quarternary salts. The acid addition salts areformed from a compound of Formula I and a pharmaceutically acceptableinorganic or organic acid including but not limited to hydrochloric,hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, citric,malonic, fumaric, maleic, oxalic acid, sulfamic, or tartaric acids.Quaternary salts include chloride, bromide, iodide, sulfate, phosphate,methansulfonate, citrate, acetate, malonate, fumarate, oxalate,sulfamate, and tartrate. Halogen means bromine, chlorine, fluorine andiodine.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions apply unless indicated otherwise:

An “aryl” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Examples, without limitation, ofheteroaryl groups are furyl, thienyl, benzothienyl, thiazolyl,imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzthiazolyl,triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl,pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl,carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, andpyrazinyl.

As used herein, a “non-aromatic heterocycle” group refers to amonocyclic or fused ring group having in the ring(s) one or more atomsselected from the group consisting of nitrogen, oxygen and sulfur. Therings may also have one or more double bonds. However, the rings do nothave a completely conjugated pi-electron system. Examples, withoutlimitation, of non-aromatic heterocycle groups are azetidinyl,piperidyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl,morpholinyl, thiomorpholinyl, tetrahydropyranyl, oxazolidonyl,oxazolonyl, 2-pyrrolidinonyl, hydantoinyl, meleimidyl andoxazolidinedionyl.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. For example, the term “C₁₋₆ alkyl” as usedherein and in the claims (unless specified otherwise) mean straight orbranched chain alkyl groups such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, amyl, hexyl and the like.

A “cycloalkyl” group refers to a saturated all-carbon monocyclic orfused ring (i.e., rings which share and adjacent pair of carbon atoms)group wherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,and adamantane.

A “cycloalkenyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings contains one or more carbon-carbon doublebonds but does not have a completely conjugated pi-electron system.Examples, without limitation, of cycloalkenyl groups are cyclopentene,cyclohexadiene, and cycloheptatriene.

An “alkenyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbondouble bond.

An “alkynyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbontriple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “O-carboxy” group refers to a R″C(O)O-group, with R″ as definedherein.

An “amino” group refers to an —NH₂ group.

A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x)selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl, and heteroalicyclic and R^(y) selected from hydrogen oralkyl.

A “cyano” group refers to a —CN group.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present invention are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Compounds of Formula I can be prepared either by coupling2-substituted-benzimidazoles (II), where X is a halide or sulfonate suchas mesylate or tosylate, with 2-oxo-imidazopyridines or2-oxo-imidazopyrimidines (III) in the presence of base, preferablyphosphazene bases such as t-butylimino-tri(pyrrolidino)phosphorane(BTPP), cesium carbonate or sodium hydride (Scheme I-A) or by reactingIa with a R₂-LG, where LG is a leaving group, preferably a halide orsulfonate such as mesylate or tosylate (Scheme I-B). Alternatively,compounds of Formula I can be synthesized according to the proceduredescribed in Scheme I-C. Coupling of 2-substituted-benzimidazoles (IV)containing protecting groups (P) such as p-methoxybenzyl, mesyl, or2-cyanoethyl with 2-oxo-imidazopyridines or 2-oxo-imidazopyrimidines inthe presence of base is followed by removal of the protecting groupusing appropriate conditions. Deprotection can be accomplished bytreatment with ceric ammonium nitrate (CAN), treatment with hydrazine ortetrabutylammonium fluoride (TBAF), or treatment with potassiumtert-butoxide to respectively remove p-methoxybenzyl, mesyl, or2-cyanoethyl groups and give intermediates V. Compounds of Formula I canthen be prepared by reacting V with R₁-LG where LG is a leaving grouppreferably a halide or sulfonate such as mesylate or tosylate.

The synthesis of 2-substituted-benzimidazoles (IIa) is shown in SchemesII A-C. Treatment of substituted or unsubstituted2-hydroxymethylbenzimidazole (VI) with 1.05 equivalents of base,preferably sodium hydride or cesium carbonate, followed by the additionof R₁-LG, where LG is a leaving group such as halide or sulfonate, givescompound VII. Treatment of the alcohol with thionyl chloride provides2-chloromethyl-benzimidazole Ia (Scheme II-A). In a separate syntheticroute, depicted in Scheme II-B, 2-fluoro-nitrobenzene (VIII) reacts withan amine to afford compound IX. Reduction of the nitro group provides aphenylenediamine derivative X which is cyclized with glycolic acid in4-6 N HCl to give alcohol VII. Alternatively, 2-amino-nitrobenzene (IX)is acylated with 2-benzyloxyacetyl chloride to provide XI (Scheme II-C).Reduction of the nitro group followed by ring closure in ethanol in thepresence of catalytic amount of acetic acid provides XII. Removal of thebenzyl group using boron tribromide or palladium hydroxide on carbon andcyclohexene yields VII.

Preparation of compounds IVa-IVd containing protecting groups isdepicted in Schemes IID-F. In Scheme II-D, 2-chloromethylbenzimidazolereacts with methane sulfonyl chloride (Ms-Cl) and triethylamine to givecompound IVa. The chloride can be refluxed with potassium iodide inacetone to produce compound IVb. A p-methoxybenzyl protecting group isinstalled in Scheme II-E. Reaction of 4-methoxybenzyl chloride with2-hydroxymethyl benzimidazole (VI) in the presence of base, preferablysodium hydride, gives compound of Formula XIV. Treatment of alcohol XIVwith (bromomethylene)dimethylaiimonium bromide provides compound IVc.Compound IVd can be prepared as described in Scheme II-F. Michaeladdition of 2-hydroxymethylbenzimidazole (VI) with acrylonitrile yieldscompound XV which is then converted to the chloride IVd by treatmentwith thionyl chloride.

2-Oxo-imidazopyridines and 2-oxo-imidazopyrimidines can be synthesizedusing the procedure depicted in Scheme III. Displacement of Z, which isa halide, preferably chlorine, or an alkoxy group, preferably methoxy,of nitropyridines XVI (2-chloro-3-nitro-pyridine,4-alkoxy-3-nitropyridine and 3-alkoxy-2-nitropyridine) with an aminegives XVII (Scheme III-A). Reduction of the nitro group and cyclizationof the resulting diamine (XVIII) using phosgene/polyvinylpyridine,carbonyldiimidazole or urea provides N3-substituted2-oxo-imidazopyridine III. N-substituted 2-oxo-5-imidazo-pyridines IIIaare prepared from known compound XIX by N-alkylation and deprotection ofthe t-butoxycarbonyl with aqueous sodium hydroxide (Scheme III-B). Onthe other hand, N-alkylation of XX and acid hydrolysis of theisopropenyl group gives 2-oxo-imidazo-6-pyridine IIIb (Scheme III-C).2-Oxo-imidazopyrimidines (IIIc) can be prepared directly by reacting2-oxo-imidazopyrimidine (XXI) with R₂-LG where LG is a leaving group asdescribed above, to give IIIc, as illustrated in Scheme III-D.Alternatively, 4,6-dichloro-5-nitropyrimidine (XXII) is treated with anamine to generate XXIII (Scheme III-E). Catalytic reduction of both thenitro group and the carbon-chlorine bond, and cyclization of theresulting diamine (XIV) with phosgene provides IIId.

Experimental Section

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on aBruker Avance 500, AC-300, Bruker DPX-300 or a Varian Gemini 300 10spectrometer. All spectra were determined in CDCl₃, CD₃OD, or DMSO-d₆and chemical shifts are reported in δ units relative totetramethylsilane (TMS). Splitting patterns are designated as follows:s, singlet; d, doublet; t, triplet; m, multiplet; b, broad peak; dd,doublet of doublets; dt, doublet of triplets. Mass spectroscopy wasperformed on a Finnigan SSQ 7000 quadrupole mass spectrometer in bothpositive and negative electrospray ionization (ESI) modes or on a LC-MSusing Shimadzu LC-10AS with micromass platform LC single quadrupole massspectrometer in positive electrospray ionization. High resolution massspectroscopy was recorded using a Finnigan MAT 900. Infrared (IR)spectra were recorded on a Perkin-Elmer system 2000 FT-IR. Elementalanalysis was performed with a Perkin-Elmer series II, model 2400 CHN/O/Sanalyzer. Column chromatography was performed on silica gel from VWRScientific. Preparative HPLC was performed using a Shimadzu LC-8A on aC18 column eluted with mixture of MeOH in water with 0.1%trifluoroacetic acid.

Abbreviations used in the experimental section:

BEMP:2-t-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine

BTPP: t-butylimino-tri(pyrrolidino)phosphorane

CAN: ceric ammonium nitrate

DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene

DIEA: N,N-diisopropylethylamine

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

Et₂O: diethyl ether

EtOAc: ethyl acetate

EtOH: ethyl alcohol

MeOH: methanol

Prep HPLC: preparative high performance liquid chromatography

Prep TLC: preparative thin layer chromatography

TBAF: tetrabutylammonium fluoride

TFA: trifluoroacetic acid

THF: tetrahydrofuran

I. Preparation of Benzimidazoles:

Compounds 1-25, 59-111, and 138-143 are benzimidazole intermediatessynthesized according to the procedures described in Scheme II.

To a solution of 2-hydroxymethylbenzimidazole (29.63 g, 200 mmol) in amixture of DMF/THF (150 mL, 1:1) was added sodium hydride (60% inmineral oil, 8.4 g, 210 mmol) in several portions at room temperature.After stirring for 1 hour, 4-bromobutyronitrile (29.6 g, 200 mmol) wasadded and the resulting solution was stirred at 80° C. for 16 hours. Thesolvent was evaporated and the residue diluted with water and extractedwith EtOAc. The combined extracts were dried over MgSO₄ and evaporated.The residue was purified by flash chromatography (gradient,EtOAc/hexane, 1:1 to 2:1, then EtOAc/MeOH, 10:1) to give 22.11 g (51%yield) of 1 as a white solid.

¹H NMR (CDCl₃) δ 2.27-2.32 (m, 2 H), 2.41 (t, J=6.0 Hz, 2 H), 4.41 (t,J=7.2 Hz, 2 H), 7.26-7.38 (m, 3 H), 7.67-7.70 (m, 1 H); MS m/e 216(MH⁺).

General Procedure for Converting 2-Hydroxymethyl-benzimidazoles to2-Chloromethyl-benzimidazoles.

The procedure described below was used for the synthesis of compounds 2,4, 9, 11A+11B, 15, 19, 23, 25, 70, 72, 76, 81, 88, 92, 94, 96, 98, 100,102, 108, and 111 and 143.

To alcohol 1 (22 g, 102.2 mmol) suspended in CH₂Cl₂ (100 mL),thionylchloride (15.81 g, 132.9 mmol) was slowly added with ice-water bathcooling. The ice bath was removed. The solution was stirred at roomtemperature for 1 hour and then evaporated. The residue was trituratedwith EtOAc to give a nearly quantitative yield of 2 as light graypowder.

¹H NMR (CDCl₃) δ 2.32-2.38 (m, 2 H), 2.70 (t, J=7.3 Hz, 2 H), 4.69 (t,J=7.6 Hz, 2 H), 5.33 (s, 2 H), 7.69-7.74 (m, 2 H), 7.85-7.87 (m, 1 H),8.00-8.02 (m, 1 H); MS m/e 234 (MH⁺). Anal. Calcd for C₁₂H₁₂N₃•HCl•0.25H₂O: C, 52.48; H, 4.95; N, 15.30 Found: C, 52.52; H, 4.88; N, 15.26

Compound 3 was prepared using the same procedure described for compound1, except that 4-bromobutyronitrile was replaced with3-methylbutylbromide.

¹H NMR (CDCl₃) δ 1.71-1.78 (m, 3 H), 4.28 (t, J=7.5 Hz, 2 H), 5.02 (s, 2H), 7.33-7.41 (m, 3 H), 7.75 (d, J=7.9 Hz, 2 H); MS m/e 219 (MH⁺).

Compound 4 was prepared according to the same procedure described forcompound 2.

¹H NMR (CDCl₃) δ 1.08 (d, J=6.4 Hz, 6 H), 1.83-1.89 (m, 3 H), 4.57-4.60(m, 2 H), 5.30 (s, 2 H), 7.68-7.73 (m, 2 H), 7.84-7.86 (m, 1 H),7.93-7.95 (m, 1H); MS m/e 237 (MH⁺).

A solution of 2,5-difluoronitrobenzene (15.4 g, 96.8 mmol),4-aminobutyronitrile (7.4 g, 88 mmol) and diisopropylethylamine (23 ml,132 mmol) in DMF (250 ml) was stirred at room temperature for 32 hours.After filtration, the solvent was evaporated and the orange solid wasrecrystallized from MeOH (250 ml) to afford 5 (14 g, 65% yield) asorange crystals.

¹H NMR (CDCl₃) δ 2.06-2.12 (m, 2 H), 2.54 (t, J=7.0 Hz, 2 H), 3.48-3.53(m, 2 H), 6.85-6.88 (m, 1 H), 7.27-7.31 (m, 1 H), 7.89-7.92 (m, 1 H); MSm/e 224 (MH⁺).

To a suspension of nitrile 5 (10.8 g, 48.4 mmol) and potassium carbonate(20.1 g, 145 mmol) in CH₃CN (200 ml) was added benzyloxyacetyl chloride(7.64 ml, 48.4 mmol) dropwise. After stirring at room temperature for 12hours, the mixture was diluted with EtOAc (500 ml) and filtered. Thefiltrate was washed with 1 N HCl, brine, dried over MgSO₄ andevaporated. The residue was purified by flash chromatography (gradient,EtOAc/hexane, 1:2 to 1:1) to yield 6 (7.5 g, 42% yield) as a viscouspale yellow oil.

¹H NMR (CDCl₃) δ 1.86-1.98 (m, 2 H), 2.38-2.51 (m, 2 H), 3.34-3.39 (m, 1H), 3.80-3.87 (m, 2 H), 4.06-4.14 (m, 1 H), 4.40-4.48 (m, 2 H),7.18-7.19 (m, 1 H), 7.26-7.40 (m, 5 H), 7.72-7.74 (m, 1 H); MS m/e 394(MH⁺).

In a flask equipped with a mechanical stirrer, a suspension of compound6 (6.40 g, 17.25 mmol), iron powder (2.89 g, 51.8 mmol) and ammoniumchloride (4.61 g, 86.2 mmol) in a mixture of MeOH and H₂O (200 ml, 1:1)was stirred at reflux for 4 hours. The mixture was filtered through apad of Celite and washed with MeOH. The filtrate was evaporated and theresidue was taken up in EtOAc (500 ml), washed with brine, dried overMgSO₄, and evaporated. To the residue was added CH₃CN (100 ml) andacetic acid (1 ml), and the mixture was stirred at reflux for 4 hours.The solvent was evaporated and the residue was purified by flashchromatography (gradient, EtOAc/hexane, 1:2 to 2:1) to give 7 (4.42 g,75% yield) as a viscous oil which solidified upon standing.

¹H NMR (CDCl₃) δ 2.15-2.20 (m, 2 H), 2.31 (t, J=7.0 Hz, 2 H), 4.35 (t,J=7.2 Hz, 2 H), 4.62 (s, 2 H), 4.83 (s, 2 H), 7.07-7.11 (m, 1 H),7.29-7.38 (m, 6 H), 7.43-7.46 (dd, J=2.4, 9.2 Hz, 1 H); MS m/e 324(MH⁺).

To a solution of 7 (3.23 g, 10 mmol) in CH₂Cl₂ (100 ml) at 0° C. wasadded boron tribromide (2.84 ml, 30 mmol). After stirring for 1 hour,the mixture was quenched with saturated NaHCO₃ solution with ice bathcooling and extracted with EtOAc. The combined extracts were dried overMgSO₄ and evaporated. The residue was purified by flash chromatography(gradient, CH₂Cl₂/MeOH, 40:1 to 20:1) to give 8 (1.68 g, 72% yield) asan off-white solid.

¹H NMR (CDCl₃) δ 2.25-2.30 (m, 2 H), 2.43 (t, J=7.1 Hz, 2 H), 4.41 (t,J=7.1 Hz, 2 H), 4.85 (s, 2 H), 7.04-7.081 (m, 1 H), 7.29-7.34 (m, 2 H);MS m/e 234 (MH⁺).

Compound 9 was prepared according to the same procedure described forcompound 2.

¹H NMR (CD₃OD) δ 2.30-2.36 (m, 2 H), 2.70 (t, J=7.2 Hz, 2 H), 4.67 (t,J=7.6 Hz, 2 H), 5.30 (s, 2 H), 7.49-7.54 (dt, J=2.4, 9.2 Hz, 1 H),7.62-7.64 (dd, J=2.4, 8.0 Hz, 1 H), 8.01-8.04 (dd, J=2.0, 9.2 Hz, 1 H);MS m/e 252 (MH⁺).

A mixture of 10A and 10B was prepared from5-fluoro-2-hydroxymethyl-benzimidazole using the same proceduredescribed for compound 1.

¹H NMR (CDCl₃) δ 2.26-2.30 (m, 2 H), 2.42-2.46 (m, 2 H), 4.36-4.42 (m, 2H), 4.87 (s, 2 H), 7.03-7.07 (m, 1.5 H), 7.30-7.32 (m, 1 H), 7.60-7.63(m, 0.5 H); MS m/e 234 (MH⁺).

Compounds 11A and 11B were prepared according to the same proceduredescribed for compound 2.

¹H NMR (CDCl₃) δ 2.24-2.30 (m, 2 H), 2.44-2.47 (m, 2 H), 4.32-4.39 (m, 2H), 4.829 (s, 1 H), 4.831 (s, 1 H), 7.01-7.11 (m, 1.5 H), 7.30-7.33 (dd,J=4.4, 8.8 Hz, 0.5 H), 7.40-7.42 (dd, J=2.3, 9.0 Hz, 0.5 H), 7.66-7.68(dd, J=4.8, 8.8 Hz, 0.5 H); MS m/e 252 (MH⁺).

2-Fluoronitrobenzene (35.4 g, 250.9 mmol), 3-(methylthio)propylamine(24.0g, 228.1 mmol) and potassium carbonate (47.3 g, 342 mmol) werestirred in CH₃CN (100 mL) at room temperature overnight. After stirringfor an additional hour at reflux, the mixture was cooled to roomtemperature and filtered. The filtrate was evaporated. To the residue inDMF (150 mL), magnesium monoperoxyphthalate hexahydrate (MMPP, 168 g,340 mmol) was added in several portions with ice-water cooling. Themixture was stirred at room temperature for 3 hours and the solvent wasevaporated. The residue was dissolved in CH₂Cl₂ and washed with 1 NNaOH, water, brine, dried over MgSO₄ and evaporated. The residue wastriturated with hot EtOAc to give 12 (48.7 g, 75% yield) as an orangesolid.

¹H NMR (CDCl₃) δ 2.25-2.35 (m, 2 H), 2.97 (s, 3 H), 3.17 (t, J=7.2 Hz, 2H), 3.59 (t, J=6.9 Hz, 2 H), 6.68-6.74 (m, 1 H), 6.89 (d, J=8.1 Hz, 1H), 7.45-7.51 (m, 1 H), 8.20 (dd, J=1.5, 8.7 Hz, 1 H); MS m/e 259 (MH⁺);Anal. Calcd for C₁₀H₁₄N₂O₄S: C, 46.50; H, 5.46; N, 10.84 Found: C,46.53; H, 5.54; N, 10.90.

To a suspension of 12 (48.5 g, 187.8 mmol) in a mixture of CHCl₃ andMeOH ( 150 mL, 1:3) was added 10% palladium on carbon (6 g) undernitrogen. The reduction was carried out in a Parr shaker with hydrogenpressure maintained between 40 and 60 psi for 25 minutes. The catalystwas removed by filtration through a pad of Celite and the filtrate wasevaporated to give crude 13.

¹H NMR (CD₃OD) δ 2.11-2.21 (m, 2 H), 2.98 (s, 3 H), 3.28-3.36 (m, 4 H),6.75 (dt,J=0.9, 7.2 Hz, 1 H), 6.85 (d,J=7.5 Hz, 1 H), 7.06-7.12 (m,2 H);MS m/e 229 (MH⁺).

The crude diamine 13 obtained above was stirred at reflux overnight withglycolic acid (15.7 g, 207 mmol) in 6 N HCl (150 mL). The solution wascooled in an ice bath and neutralized with concentrated NH₄OH solution,extracted with EtOAc, dried over MgSO₄ and evaporated. The residue waspurified by chromatography (gradient, EtOAc/hexane, 1:1 to EtOAc/MeOH,10:1) to give a product which crystallized from EtOAc/MeOH to afford25.7 g (51% yield in two steps) of 14.

¹H NMR (CD₃OD) δ 2.38-2.44 (m, 2 H), 2.97 (s, 3 H), 3.24 (t, J=7.6 Hz, 2H), 4.54 (t, J=7.6Hz, 2 H), 7.27 (t, J=1.1, 8.1 Hz, 1 H), 7.33 (dt,J=1.1, 8.0Hz, 1 H), 7.62 (d, J=8.1 Hz, 1 H), 7.64 (dd, J=1.0, 8.0 Hz, 1H); MS m/e 269 (MH⁺).

Compound 15 was prepared according to the same procedure described forcompound 2.

¹H NMR (CD₃OD) δ 2.46-2.52 (m, 2 H), 3.03 (s, 3 H), 3.37 (t, J=7.1 Hz, 2H), 4.77 (t, J=7.8 Hz, 2 H), 5.31 (s, 2 H), 7.68-7.73 (m, 2 H), 7.86(dd, J=2.8, 6.9 Hz, 1 H), 8.03 (dd, J=1.7, 6.1 Hz, 1 H); MS m/e 287(MH⁺).

To a solution of 2,5-difluoronitrobenzene (15.1 g, 95.06 mmol) in CH₃CN(150 mL) was added potassium carbonate (26.3 g, 190.11 mmol) and3-(methylthio)propylamine (10.0 g, 95.06 mmol). The mixture was stirredvigorously with the aid of a mechanical stirrer for 16 hours at roomtemperature. The solid was filtered and the filtrate was evaporated. Theresidue was diluted with EtOAc (600 mL) and washed with water and brine.The organic layer was dried over anhydrous MgSO₄ and evaporated to givecrude 16 as an orange solid (25 g, 70% pure).

1H NMR (CDCl₃) δ 1.97-2.01 (m, 2 H), 2.11 (s, 3 H), 2.62 (t, J=6.9 Hz, 2H), 3.43 (q, J=6.3 Hz, 2 H), 6.87 (dd, J=4.6, 9.3 Hz, 1 H), 7.22-7.24(m, 1 H), 7.85 (dd, J=3.1, 9.3 Hz, 1 H), 7.95 (bs, 1 H); MS m/e 245(MH⁺).

A solution of 16 (25 g) in MeOH (300 mL) was added to a mixture of ironpowder (12.0 g, 214.9 mmol) and ammonium chloride (19.2 g, 358.2 mmol)in water (100 mL). The reaction mixture was vigorously stirred with amechanical stirrer and heated at 90° C. for 16 hours. The mixture wasfiltered through a plug of Celite which was rinsed with hot methanol.The solvent was evaporated to give the crude diamine. LC-MS m/e 215(MH⁺).

The diamine (500 mg crude, 2.33 mmol) and glycolic acid (266 mg, 3.50mmol) were heated at reflux in 4 N hydrochloric acid (15 mL) for 16hours. The aqueous solution was cooled and neutralized with concentratedNH₄OH (15 mL). The aqueous solution was then extracted with EtOAc. Theorganic extracts were dried over anhydrous MgSO₄, filtered andevaporated. The residue was purified by flash chromatography (gradient,EtOAc/hexanes, 2:1 to EtOAc/MeOH, 10:1) to give 17 (150 mg, 25% yield).

¹H NMR (CD₃OD) δ 2.08 (s, 3 H), 2.12-2.20 (m, 2 H), 2.53 (t, J=6.9 Hz, 2H), 4.43 (t, J=6.3 Hz, 2 H), 4.85 (s, 2 H), 7.07 (dt, J=2.4, 9.2 Hz, 1H), 7.30 (dd, J =2.4, 9.3 Hz, 1 H), 7.53 (dd, J=4.6, 8.9 Hz, 1 H); MSm/e 255 (MH⁺).

To a solution of sulfide 17 (150 mg, 0.59 mmol) in DMF (5 mL) was addedmagnesium monoperoxyphthate hexahydrate (MMPP, 583 mg, 1.18 mmol). Thereaction mixture was stirred at room temperature for 16 hours. Thesolvent was evaporated, and the residue was diluted with water andextracted with EtOAc. The combined extracts were washed with saturatedaqueous sodium bicarbonate solution and dried over anhydrous MgSO₄,filtered and evaporated. The residue was purified by flashchromatography (gradient, straight EtOAc to EtOAc/MeOH, 10:1) to give 18(129 mg, 76% yield) as a white solid.

¹H NMR (CD₃OD) δ 2.37-2.47 (m, 2 H), 3.00 (s, 3 H), 3.26 (t, J=7.4 Hz, 2H), 4.55 (t, J=7.5 Hz, 2 H), 7.14 (dt, J2.4, 9.4Hz, 1 H), 7.34 (dd,J=2.4, 9.2 Hz, 1 H), 7.62 (dd, J=4.5, 8.9 Hz, 1H); IR (KBr, cm⁻¹) 3139,1624, 1591, 1489, 1478, 1446, 1416, 1308, 1270, 1143, 1134, 1047, 951,859, 802, 527, 500; MS m/e 287 (MH⁺); Anal. Calcd for C₁₂H₁₅FN₂O₃S: C,50.33; H, 5.28; N, 9.78 Found: C, 50.17; H, 5.17; N, 9.57.

Compound 19 was prepared according to the same procedure described forcompound 2.

¹H NMR (DMSO-d₆) δ 2.15-2.20 (m, 2 H), 3.00 (s, 3 H), 3.26 (t, J=7.2 Hz,2 H), 4.47 (t, J=7.8 Hz, 2 H), 5.11 (s, 2 H), 7.27 (dt, J=2.4, 9.4 Hz, 1H), 7.51 (dd, J =2.4, 9.0Hz, 1 H), 7.76 (dd, J=4.8, 9.0 Hz, 1 H); IR(KBr, cm⁻¹) 3429, 2577, 1635, 1536, 1496, 1290, 1277, 1130, 962, 927,784; MS m/e 305 (MH⁺).

To a solution of 2,5-difluoronitrobenzene (45 g, 282.86 mmol) in CH₃CN(500 mL) was added potassium carbonate (78 g, 565.72 mmol) andisoamylamine (25 g, 282.86 mmol). The reaction mixture was stirred atroom temperature for 18 hours with the aid of a mechanical stirrer. Thepotassium carbonate was filtered and the filtrate was evaporated to givean orange oil. The oil was diluted with EtOAc, washed with water andbrine, dried over MgSO₄, and evaporated. Purification by flash columnchromatography (hexanes/EtOAc, 20:1) gave 53 g (83% yield) of compound20.

¹H NMR (CDCl₃) δ 0.98 (d, J=6.5 Hz, 6 H), 1.61-1.65 (m, 2 H), 1.74-1.78(m, 1 H), 3.30 (t, J=7.3 Hz, 2 H), 6.83 (dd, J=4.6, 9.5 Hz, 1 H),7.23-7.27 (m, 1 H), 7.85 (dd, J=3.1, 9.2 Hz, 1 H).

To a solution of compound 20 (53 g, 235.14 mmol) and concentrated HCl(15 mL) in MeOH (200 mL) was added 10% palladium on carbon (5 g) and themixture was agitated under H₂ at 55 psi for 1.5 hours. The catalyst wasremoved by filtration through a pad of Celite and the filtrate wasconcentrated to give 47 g (87% yield) of diamine 21 as the HCl salt.

¹H NMR (CDCl₃) δ 0.97 (d, J=6.2 Hz, 6 H), 1.65-1.77 (m, 3 H), 3.36 (t,J=8.0 Hz, 2 H), 6.50-6.57 (m, 1 H), 6.71 (dd, J=2.7, 10.5 Hz, 1 H), 7.28(dd, J=5.5, 8.8 Hz, 1 H); MS m/e 197 (MH⁺).

A mixture of diamine 21 (47 g, 200.66 mmol) and glycolic acid (16 g,210.70 mmol) in 4 N HCl (500 mL) was stirred at reflux for 18 hours. Thereaction mixture was cooled first to room temperature and then to 0° C.The reaction was diluted with concentrated ammonium hydroxide (200 mL)until the pH was adjusted to approximately 8. The product was extractedwith EtOAc, dried over MgSO₄, and evaporated. The crude product wasrecrystallized with EtOAc/hexanes to give 27 g (37% yield) of compound22 as brown crystals.

¹H NMR (CDCl₃) δ 1.02 (d, J=6.0 Hz, 6 H), 1.68-1.75 (m, 3 H), 3.19 (bs,1 H), 4.22 (t, J=7.7 Hz, 2 H), 4.93 (s, 2 H), 7.06 (dt, J=2.2, 9.1 Hz, 1H), 7.26-7.28 (m, 1 H), 7.37 (dd, J=2.1, 8.9 Hz, 1 H); MS m/e 237 (MH⁺).

Compound 23 was prepared according to the same procedure described forcompound 2.

¹H NMR (CDCl₃) δ 1.08 (d, J=6.4 Hz, 6 H), 1.79-1.90 (m, 3 H), 4.44 (bt,J=8.2 Hz, 2 H), 5.32 (s, 2 H), 7.36 (dt, J=2.2, 8.9, 1 H), 7.54-7.59 (m,2 H); MS m/e 255 (MH⁺).

Compound 24 was prepared using the same procedure described for compound1, except that 4-biomobutyromitrile was replaced with 4-bromobutylacetate.

¹H NMR (CDCl₃) δ 1.68-1.72 (m, 2 H), 1.91-1.94 (,2 H), 2.03 (s, 3 H),4.07 (t, J=6.4 Hz, 2 H), 4.26 (t, J=7.5 Hz, 2 H), 4.86 (s, 2 H), 6.86(bs, 1 H), 7.20-7.29 (m, 3 H), 7.65 (dd, J=1.8, 6.7 Hz, 1 H); MS m/e 263(MH⁺).

Compound 25 was prepared according to the same procedure described forcompound 2.

¹H NMR (CDCl₃) δ 1.80-1.86 (m, 2 H), 2.03 (s, 3 H), 2.06-2.12 (m, 2 H),4.14 (t, J=6.1 Hz, 2 H), 4.55 (t, J=8.1 Hz, 2 H), 5.42 (s, 2 H), 7.48(t, J=7.3 Hz, 1 H), 7.55 (t, J=7.3 Hz, 1 H), 7.64 (d, J=8.5 Hz, 1 H),7.78 (d, J=8.2 Hz, 1 H); MS m/e 281 (MH⁺).

Compound 59 was prepared using the same procedure described for compound1, except that 4-bromobutyronitrile was replaced with 4-methoxybenzylchloride.

¹H NMR (CDCl₃) δ 3.77 (s, 3 H), 4.99 (s, 2 H), 5.45 (s, 2 H), 6.84 (d,J=8.6 Hz, 2 H), 7.11 (d, J=8.6 Hz, 2 H), 7.28-7.34 (m, 3 H), 7.75 (d,J=6.8, 1 H); MS m/e 269 (MH⁺).

Compound 59 (4,75 g, 17.7 mmol) was combined with CH₂Cl₂ (100 mL) andthe mixture was treated with (bromomethylene)dimethylammonium bromide(5.25 g, 23.0 mmol). The reaction was stirred at room temperature for 30minutes and then filtered to isolate a white solid. The solid was rinsedwith CH₂Cl₂, then with diethyl ether. The solid was triturated withwater (50 mL), isolated by filtration, rinsed with water, then withacetone, and finally with Et₂O. The white powder was labeled crop 1 andset aside. All liquids were combined and concentrated in vacuo to givean off-white solid which was triturated with a mixture of acetone (50mL) and Et₂O (300 mL). The liquid was decanted and the solid wassuspended in acetone and isolated by filtration to give crop 2. Crops 1and 2 were determined to be spectroscopically identical and werecombined to give 6.65 g (91% yield) of compound 60 as a white powder.

¹H NMR (DMSO-d₆) δ 3.72 (s, 3 H), 5.18 (s, 2 H), 5.68 (s, 2 H), 6.92 (d,J=8.7 Hz, 2 H), 7.29 (d, J=8.7 Hz, 2 H), 7.44-7.47 (m, 2 H), 7.62-7.63(m, 1 H), 7.78-7.80 (m, 1 H); MS m/e 332 (MH⁺).

Compound 61 was prepared according to the same procedure described forcompound 16 using 3-methoxypropylamine instead of3-(methylthio)propylamine.

¹H NMR (CDCl₃) δ 1.95-2.00 (m, 2 H), 3.37 (s, 3 H), 3.39-3.43 (m, 2 H),3.52 (t, J=5.7 Hz, 2 H), 6.61 (t, J=8.2 Hz, 1 H), 6.86 (d, J=8.8 Hz, 1H), 7.41 (t, J=7.9 Hz, 1 H), 8.14 (dd, J=1.4, 8.7 Hz, 1 H), 8.26 (bs, 1H); MS m/e 211 (MH⁺).

Compound 62 was prepared from compound 61 according to the sameprocedure described for compound 13 and was used immediately uponisolation.

MS m/e 181 (MH⁺).

Compound 63 was prepared from compound 62 according to the sameprocedure described for compound 14.

¹H NMR (CDCl₃) δ 2.09-2.14 (m, 2 H), 3.30 (t, J=5.7 Hz, 2 H), 3.33 (s, 3H), 4.35 (t, J=6.9 Hz, 2 H), 4.89 (s, 2 H), 7.22-7.26 (m, 2 H),7.35-7.37 (m, 1 H), 7.69-7.70 (m, 1 H); MS m/e 221 (MH⁺).

A solution of compound 63 (1.50 g, 6.81mmol) in CH₃CN (20 mL) wastreated with (bromomethylene)dimethylammonium bromide. The reactionmixture was stirred at room temperature for 18 hours. The reaction wasquenched with H₂O (3 mL) and the solvent was evaporated and dried undervacuum to give compound 64 which was used immediately upon isolation.

MS m/e 283, 285 (MH⁺).

Compound 65 was prepared according to the same procedure described forcompound 1, except that 4-bromobutyronitrile was replaced with benzyl4-bromobutylether.

¹H NMR (CD₃OD) δ 1.65-1.71 (m, 2 H), 1.94-1.99 (m, 2 H), 3.52 (t, J=6.2Hz, 2 H), 4.36 (t, J=7.7 Hz, 2 H), 4.47 (s, 2 H), 4.84 (s, 2 H),7.22-7.27 (m, 3 H), 7.27-7.31 (m, 4 H), 7.48 (d, J=7.4 Hz, 1 H), 7.61(dd,J=1.4, 7.1 Hz, 1 H); MS m/e 311 (MH⁺).

Compound 66 was prepared according to the same procedure described forcompound 64.

MS m/e 373, 375 (MH⁺).

To a suspension of 1,2-phenylenediamine (50 g, 462 mmol) in THF (150 mL)cooled at 0C was slowly added a solution of benzyloxyacetyl chloride(171 g, 924 mmol) in THF (100 mL). The reaction mixture was stirred for3 hours. The reaction mixture was cooled to 0° C. with an ice bath and4N HCl (300 mL) was slowly added to the reaction mixture. The ice bathwas removed and the mixture was heated at reflux for 18 hours. Themajority of the THF was evaporated. The aqueous material was neutralizedwith 10 N NaOH, extracted with EtOAc, dried over MgSO₄, and evaporatedto give a tan solid. The solid was recrystallized from EtOAc to give 45g (41% yield) of compound 67. ¹H NMR (CD₃OD) δ 4.65 (s, 2 H), 4.77 (s, 2H), 7.22-7.41 (m, 7 H), 7.56 (dd, J 3.2, 6.1 Hz, 2 H); MS m/e 239 (MH⁺).

To a solution of compound 67 (6.00 g, 25.18 mmol) in DMF (50 mL) wasadded sodium hydride (60% dispersion in mineral oil, 1.46 g, 36.52mmol). The reaction mixture was cooled to 0° C. and stirred for 30minutes. To the cooled mixture 1 -bromo-3 -chloropropane (5.3 5 g, 32.99 mmol) was added and the reaction mixture was stirred for 4.5 hours.The mixture was diluted with H₂O (75 mL) and extracted with Et₂O (3×300mL). The combined organic extracts were dried over MgSO₄ and evaporated.Purification by flash column chromatography on silica (gradient,hexanes/FtOAc 2:1 to 1:1) gave 6.86 g (87% yield) of compound 68.

¹H NMR (CDCl₃) δ 2.22-2.36 (m, 2 H), 3.53 (t, J=6.0 Hz, 2 H), 4.45 (t,J=7.0 Hz, 2 H), 4.62 (s, 2 H), 4.90 (s, 2 H), 7.28-7.44 (m, 7 H),7.42-7.48 (m, 1 H), 7.79-7.82 (m, 1 H); MS m/e 315, 317 (MH⁺).

A solution of compound 68 (4.00 g, 12.71 mmol) in CH₂Cl₂ (75 mL) wascooled to 0° C. with an ice bath. To this solution was added borontribromide (0.99M in CH₂Cl₂, 20 mL, 19.76 mmol) slowly via syringe. Thereaction mixture was stirred at 0° C. for 2 hours. The reaction wasquenched at 0° C. with MeOH (75 mL). The solvent was evaporated with aroom temperature rotary evaporator bath. More MeOH was added and wasagain evaporated. The resulting solid was dried under high vacuum for 48hours to give 3.70 g (95% yield) of compound 69.

¹H NMR (CD₃OD) δ 2.39-2.44 (m, 2 H), 3.72 (t, J=6.0 Hz, 2 H), 4.61 (t,J7.2 Hz, 2 H), 5.19 (s, 2 H), 7.62-7.68 (m, 2 H), 7.80-7.82 (m, 1 H),7.93-7.95 (m, 1 H); MS m/e 225, 227 (MH⁺).

Compound 70 was prepared according to the same procedure described forcompound 2.

MS m/e 244 (MH⁺).

Compound 71 was prepared according to the same procedure described forcompound 1 using 1,4-dibromobutane and the reaction was carried out at0° C.

¹H NMR (CD₃OD) δ 1.91-1.95 (m, 2 H), 2.01-2.08 (m, 2 H), 3.48 (t, J=6.6Hz, 2 H), 4.38 (t, J=7.4 Hz, 2 H), 4.86 (s, 2 H), 7.23-7.27 (m, 1 H),7.29-7.32 (m, 1H), 7.54 (d, J=8.0 Hz, 1 H), 7.62 (d, J=8.0 Hz, 1 H); MSm/e 282, 284 (MH⁺).

Compound 72 was prepared according to the same procedure described forcompound 2 and was used immediately upon isolation.

Compound 73 was prepared according to the same procedure described forcompound 1 using 1,3 dibromopropane and the reaction was carried out at0° C.

¹H NMR (CDCl₃) δ 2.42-2.47 (m, 2 H), 3.43 (t, J=6.1 Hz, 2 H), 4.43 (t,J=7.0 Hz, 2 H), 4.94 (s, 2 H), 7.25-7.32 (m, 2 H), 7.42-7.44 (m, 1 H),7.68-7.70 (m, 1 H); MS m/e 268, 270 (MH⁺).

2-Propanethiol (305 mg, 4.00 mmol) and sodium hydride (60% dispersion inmineral oil, 240 mg, 6.00 mmol) were stirred together in DMF (20 mL) andthen cooled to 0° C. To this mixture was added compound 73 (542 mg, 2.00mmol) and the reaction mixture was allowed to warm to room temperatureover 2 hours. The reaction mixture was quenched with water and extractedwith EtOAc. The combined organic extracts were washed with water andbrine, dried over MgSO₄, and evaporated. Purification by columnchromatography (gradient, CH₂Cl₂/MeOH, 40:1 to 20:1) gave 310 mg (59%yield) of compound 74 as an off-white oil.

¹H NMR (CD₃OD) δ 1.22 (d, J=6.7 Hz, 6 H), 2.10-2.18 (m, 2 H), 2.58 (t,J=7.0 Hz, 2 H), 2.90-2.93 (m, 1 H), 4.45 (t, J=7.3 Hz, 2 H), 4.87 (s, 2H), 7.23-7.32 (m, 2 H), 7.55 (d, J=8.0 Hz, 1 H), 7.62 (d, J=7.9 Hz, 1H); MS m/e 265 (MH⁺).

Compound 75 was prepared from compound 74 according to the sameprocedure described for compound 18.

¹H NMR (CD₃Cl) δ 1.32-1.36 (m, 6 H), 2.44-2.50 (m, 2 H), 3.00-3.02 (m, 2H), 3.06-3.10 (m, 1 H), 4.48 (t, J=7.3 Hz, 2 H), 4.87 (s, 2 H),7.23-7.30 (m, 2 H), 7.42 (d, J=7.7 Hz, 1 H), 7.65 (d, J=7.8 Hz, 1 H); MSm/e 297 (MH⁺).

Compound 76 was prepared according to the same procedure described forcompound 2 and was used immediately upon isolation.

To a solution of compound 67 (18.25 g, 76.59 mmol) in DMF (85 mL) wasadded sodium hydride (60% dispersion in mineral oil, 3.37 g, 84.25mmol). The reaction mixture was stirred for 30 minutes and then cooledto 0° C. 1,3-Dibromopropane was slowly added to the cooled solution. Thetemperature was raised to room temperature after 20 minutes as nostarting material remained. The reaction mixture was diluted with H₂Oand extracted with EtOAc. The combined organic extracts were dried overMgSO₄ and evaporated. Column chromatography (hexanes/EtOAc, 2:1) gave5.2 g of a 60/40 mixture of the desired bromide compound 77A (8% yield)and an undesired elimination product 77B. This mixture was used in thenext step without further purification.

Bromide 77A: MS m/e 360, 361 (MH⁺);

Elimination product 77B: MS m/e 279 (MH⁺).

To a solution of ethanethiol (1.04 g, 16.77 mmol) in DMF (60 mL) wasadded sodium hydride (60% dispersion in mineral oil, 670 mg, 16.77mmol). The mixture was stirred for 15 minutes at room temperature andthen cooled to 0° C. In a separate flask, the mixture containingcompounds 77A and 77B (5.2 g mixture, 3.0 g, 8.3 8 mmol) as dissolved inDMF (10 mL), cooled to 0° C. and added slowly to the ethanethiolmixture. The reaction mixture was stirred for 1 hour while thetemperature was slowly allowed to rise to room temperature. The DMF wasevaporated under reduced pressure. The residue was dissolved in EtOAcand washed with H₂O. The organic layer was dried over MgSO₄ andevaporated. This material containing compound 78 was used immediately asa mixture without further purification.

Compound 79 was prepared from crude 78 according to the same procedureas compound 18 and was purified by flash column chromatography on silica(gradient, EtOAc/hexanes, 2:1 to straight EtOAc).

¹H NMR (CDCl₃) δ 1.21 (t, J=7.5 Hz, 3 H), 2.35-2.42 (m, 2 H), 2.73 (q,J=7.5 Hz, 2 H), 2.84-2.88 (m, 2 H), 4.43 (t, J=7.2 Hz, 2 H), 4.60 (s, 2H), 4.87 (s, 2 H), 7.27-7.34 (m, 5 H), 7.42 (dd, J=1.5, 7.0Hz, 1 H),7.77 (dd, J=1.6, 6.9Hz, 1 H), 8.00(s,2H); MS m/e 373 (MH⁺).

A solution of compound 79 (1.95 g, 5.24 mmol) in CH₂Cl₂ (50 mL) wascooled to 0° C. with an ice bath. To this solution was added borontribromide (0.99 M in CH₂Cl₂, 9.0 mL, 9.00 mmol) slowly via syringe. Thereaction mixture was stirred for 40 minutes at 0° C. before quenching at0C by cautious addition of anhydrous MeOH (50 mL). The solvent wasevaporated with a room temperature rotary evaporator bath. Moreanhydrous MeOH was added and the solvent was again evaporated. Theresulting solid was dried under high vacuum for 48 hours to give 1.82 g(96% yield) of compound 80.

¹H NMR (DMSO-d₆) δ 1.22 (t, J=7.4 Hz, 3 H), 2.23-2.89 (m, 2 H), 3.11 (q,J 7.4 Hz, 2 H), 3.29 (t, J=7.7 Hz, 2 H), 4.53 (t, J=7.5 Hz, 2 H), 5.08(s, 2 H), 7.58-7.65 (m, 2 H), 7.80 (dd, J=1.0, 7.3 Hz, 1 H), 8.04 (d,J=7.75 Hz, 1 H); MS m/e 283 (MH⁺).

Compound 81 was prepared according to the same procedure described forcompound 2.

MS m/e 301 (MH⁺).

To a solution of compound 67 (1.43 g, 6.00 mmol) in DMF (25 mL) wasadded sodium hydride (60% dispersion in mineral oil, 260 mg, 6.60 mmol)and the mixture was cooled to 0° C. To the mixture was added4-bromo-1-1-butene (972 mg, 7.20 mmol) and the mixture was allowed tostir at room temperature for 18 hours. The reaction mixture was quenchedwith H₂O and extracted with EtOAc. The organic extracts were washed withwater and then brine, dried over MgSO₄, and evaporated. Flash columnchromatography (gradient, hexanes/EtOAc, 4:1 to 1: 1) gave 5 80 mg (33%yield) of compound 82 as a viscous oil.

¹H NMR (CDCl₃) δ 2.55-2.59 (m, 2 H), 4.31 (t, J=7.5 Hz, 2 H), 4.59 (s, 2H), 4.88 (s, 2 H), 5.01 (d, J=7.8 Hz, 1 H), 5.04 (d, J=10.4 Hz, 1 H),5.71-5.80 (m, 1 H), 7.26-7.39 (m, 8 H), 7.79 (d, J=7.6 Hz, 1 H); MS m/e293 (MH⁺).

To a solution of compound 82 (468 mg, 1.92 mmol) and water (71 mg, 3.93mmol) in DMSO (5 mL) was added N-bromosuccinimide (NBS, 700 mg, 3.93mmol) at room temperature and the mixture was stirred for 1 hour. Theresulting solution was diluted with EtOAc and washed with H₂O. Theorganic extracts were dried with MgSO₄ and evaporated. The residue waspurified by flash chromatography (gradient, hexane:EtOAc 3:1 to 1:2) togive 214 mg (56% yield) of compound 83 as a off-white viscous oil.

¹H NMR (CDCl₃) δ 1.90-1.97 (m, 1 H), 2.12-2.18 (m, 1 H), 3.22-3.30 (m, 2H), 3.61-3.66 (m, 1 H), 4.38-4.50 (m, 2 H), 4.59-4.64 (m, 2 H),4.87-4.92 (m, 2 H), 7.28-7.37 (m, 7 H), 7.42-7.46 (m, 1 H), 7.78-7.80(m, 1 H); MS m/e 389, 391 (MH⁺).

A mixture of compound 83 (214 mg, 0.55 mmol) and sodium azide (107 mg,1.65 mmol) in DMF (5 mL) was stirred at 50° C. for 1 hour. The resultingsolution was diluted with EtOAc and washed with water. The organicextracts were dried with MgSO₄ and evaporated to give 190 mg (98% yield)of compound 84 as a off-white viscous oil.

¹H NMR (CDCl₃) δ 1.84-1.91 (m, 1 H), 2.02-2.09 (m, 1 H), 3.08-3.14 (m, 2H), 3.52-3.56 (m, 1 H), 4.36-4.41 (m, 1 H), 4.44-4.50 (m, 1 H),4.60-4.67 (m, 2 H), 4.88-4.93 (m, 2 H), 7.26-7.38 (m, 7 H), 7.42-7.44(m, 1 H), 7.79-7.81 (m, 1 H); MS m/e 352 (MH⁺).

Compound 85 was prepared from compound 84 according to the samereduction procedure described for compound 13.

¹H NMR (CD₃OD) δ 1.86-1.94 (m, 1 H), 2.03-2.10 (m, 1 H), 2.70-2.74 (m,J=3.2, 12.8 Hz, 1 H), 2.84-2.88 (dd, J=3.2, 12.8 Hz, 1 H), 3.70-3.75 (m,1 H), 4.44-4.54 (m, 2 H), 4.60-4.65 (m, 2 H), 4.88-4.93 (m, 2 H),7.27-7.38 (m, 7 H), 7.59 (d, J=8.0 Hz, 1 H), 7.65 (d, J=8.0 Hz, 1 H); MSm/e 326 (MH⁺).

A solution of compound 85 (162 mg, 0.50 mmol), carbonyldiimidazole (89mg, 0.55 mmol) and pyridine (198 mg, 2.50 mmol) in CH₂Cl₂ (5 mL) wasstirred at room temperature for 2 hours. The mixture was diluted withCH₂Cl₂ and washed with water. The organic extracts were dried over MgSO₄and evaporated. The residue was purified by flash chromatography(gradient, CH₂Cl₂:MeOH, 40:1 to 20:1) to give 130 mg (74% yield) ofcompound 86 as a off-white viscous oil.

¹H NMR (CD₃OD) δ 2.16-2.21 (m, 2 H), 3.06-3.09 (m, 1 H), 3.52-3.59 (m, 1H), 4.41-4.50 (m, 2 H), 4.58-4.65 (m, 3 H), 4.80-4.84 (m, 2 H),7.26-7.38 (m, 6 H), 7.55-7.58 (m, 1 H), 7.82-7.85 (m, 1 H), 8.51-8.53(m, 1 H); MS m/e 352 (MH⁺).

Compound 86 (130 mg, 0.37 mmol), palladium hydroxide on carbon(Pearlman's catalyst, 50 mg), EtOH (2 mL) and cyclohexene (1 mL) werestirred at reflux for 1 hour. The reaction mixture was filtered througha pad of Celite. The filtrate was concentrated and purified by flashcolumn chromatography (gradient, CH₂Cl₂/MeOH, 30:1 to 10:1) to give 20mg (21% yield) of compound 87 as a viscous white oil.

¹H NMR (CD₃OD) δ 2.26-2.33 (m, 2 H), 3.21-3.24 (m, 1 H), 3.65 (t, J=8.8Hz, 1 H), 4.50-4.54 (m, 2 H), 4.67-4.70 (m, 1 H), 4.89-4.92 (m, 2 H),7.24-7.34 (m, 2 H), 7.57 (d, J=8.0 Hz, 1 H), 7.63 (d, J=7.9 Hz, 1 H); MSm/e 294 (MH⁺).

Compound 88 was prepared according to the same procedure described forchloride 2 and was used immediately upon isolation.

To a solution of 2-(chloromethyl)benzimidazole (80 g, 0.48 mol) andmethanesulfonyl chloride (58.3 mL, 0.75 mol) in CH₂Cl₂ (0.5 L),triethylamine (136 mL, 0.97 mol) was added dropwise under nitrogen. Theresulting mixture was stirred at room temperature for 6 hours. Themixture was filtered and the filtrate was evaporated. The residue wastriturated with MeOH and filtered to afford 74.9 g (64% yield) ofcompound 89 as a brown solid.

¹H NMR (CDCl₃) , 3.44 (s, 3 H), 5.11 (s, 2 H), 7.40-7.49 (m, 2 H),7.76-7.82 (m, 1 H), 7.85-7.91 (m, 1H); IR (KBr, cm⁻¹) 3027, 2920, 1371,1349, 1177, 1144, 1059; MS m/e 245 (MH⁺); Anal. Calcd for C₉H₉ClN₂O₂S:C, 44.18; H, 3.71; N, 11.45 Found: C, 44.09; H, 3.57; N, 11.49.

A solution of potassium iodide (206 g, 1.24 mol) and compound 89 (74.8g, 0.414 mol) in acetone (1 L) was stirred at reflux under nitrogen for4 hours. The solid was filtered and the filtrate was evaporated. Thecrude product was triturated in MeOH and filtered to give 83 g (60%yield) of compound 90 as a solid.

¹H NMR (CDCl₃) δ 3.48 (s, 3 H), 4.97 (s, 2 H), 7.40-7.50 (m, 2 H),7.75-7.85 (m, 2 H); IR (KBr, cm⁻¹) 3022, 2916, 1366, 1173, 1055, 966,763, 745; MS m/e 336 (MH⁺); Anal. Calcd for C₉H₉IN₂O₂S: C, 32.16; H,2.70; N, 8.33 Found: C, 32.05; H, 2.63; N, 8.22.

Compound 91 was prepared according to the Michael addition proceduredescribed by Popov, I. I. in Khim Geterotskl. Soedin. 1996, 6, 781-792.

¹H NMR (CDCl₃) δ 3.08 (t, J=6.8 Hz, 2 H), 4.63 (t, 3 6.8 Hz, 2 H), 4.77(d, J 5.7 Hz, 2 H), 5.73 (t, J=5.7 Hz, 1 H), 7.17-7.28 (m, 2 H), 7.64(d, J=1.2 Hz, 1 H), 7.70 (d, J=1.2 Hz, 1H);

MS m/e 202 (MH⁺); Anal. Calcd for C₁₁H₁₁N₃O: C 65.66; H, 5.51; N, 20.88Found: C, 65.94; H, 5.57; N, 21.08.

Compound 92 was prepared according to the same procedure described forcompound 2.

¹H NMR (CDCl₃) δ 3.02 (t, J=7.0Hz, 2 H), 4.65 (t, J=7.0 Hz, 2 H), 4.99(s, 2 H), 7.34-7.44 (m, 3 H), 7.79-7.82 (m, 1 H); MS m/e 220 (MH⁺);Anal. Calcd for C₁₁H₁₀ClN₃: C, 60.09; H, 4.65; N, 19.13 Found: C, 60.09;H,4.65; N, 19.11.

Compound 93 was prepared according to the same procedure described forcompound 1 except that 4-bromobutyronitrile was replaced with ethyl4-bromobutyrate.

¹H NMR (CDCl₃) 5 1.24 (t, J=7.0 Hz, 3 H), 2.15-2.22 (m, 2 H), 2.38-2.42(m, 2 H), 4.12 (q, J=7.1 Hz, 211), 4.29-4.34 (m, 211), 4.96 (s, 211),7.22-7.30 (m, 2 H), 7.38-7.43 (m, 1 H), 7.66-7.70 (m, 1 H); MS m/e 250(MH⁺).

Compound 94 was prepared according to the same procedure described forchloride 2 and was used immediately upon isolation.

Compound 95 was prepared according to the same procedure described forcompound 1 except that 4-bromobutyronitrile was replaced with1-bromo-4-fluorobutane.

¹H NMR (DMSO-d,) 8 1.65-1.75 (m, 2 H), 1.85-1.90 (m, 2 H), 4.32 (t,J=7.5 Hz, 2 H), 4.41 (t, J=6.0 Hz, 1 H), 4.51 (t, J=6.0 Hz, 1H), 4.71(d, J=5.8 Hz, 2 H), 5.62 (t, J=5.8 Hz, 1 H), 7.18 (t, J=7.0 Hz, 1 H),7.23 (t, J=6.3 Hz, 1 H), 7.56-7.60 (m, 2 H); MS m/e 222 (MH⁺).

Compound 96 was prepared according to the same procedure described forchloride 2 and was used immediately upon isolation.

Compound 97 was prepared according to the same procedure described forcompound 1 except that 4-bromobutyronitrile was replaced with 1-bromo-4,4,4-trifluorobutane.

¹H NMR (DMSO-d₆) δ 1.99-2.05 (m, 2 H), 2.34-2.40 (m, 2 H), 4.35-4.38 (m,2 H), 4.73 (s, 2 H), 7.20 (t, J=7.2 Hz, 1 H), 7.26 (t, J=7.4 Hz, 1 H),7.60-7.63 (m, 1 H), 7.96 (s, 1 H); MS m/e 258 (MH⁺).

Compound 98 was prepared according to the same procedure described forchloride 2 and was used immediately upon isolation.

Compound 99 was prepared according to the same procedure described forcompound 1 except that 4-bromobutyronitrile was replaced with4-methylsulfonylbenzyl bromide.

¹H NMR (DMSO-d₆) 3.16 (s, 3 H), 4.75 (d, J=5.6Hz, 2 H), 5.70 (s, 2 H),5.73-5.75 (m, 1 H), 7.17-7.21 (m, 2 H), 7.36-7.38 (m, 1 H), 7.42 (d,J=8.2 Hz, 2 H), 7.64-7.65 (m, 1 H), 7.87 (d, J=8.2 Hz, 1 H); MS m/e 316(MH⁺).

Compound 100 was prepared according to the same procedure described forchloride 2 and was used immediately upon isolation.

Compound 101 was prepared according to the same procedure described forcompound 1 except that 4-bromobutyronitrile was replaced with4-fluorobenzyl bromide.

¹H NMR (DMSO-d₆) δ 4.74 (s, 2 H), 5.55 (s, 2 H), 7.13-7.18 (m, 3 H),7.28-7.30 (m, 2 H), 7.38-7.40 (m, 1 H), 7.59-7.63 (m, 1 H); MS m/e 256(MH⁺).

Compound 102 was prepared according to the same procedure described forchloride 2 and was used immediately upon isolation.

Compound 103 was prepared according to the same procedure as compound 1except that 4-bromobutyronitrile was replaced with4-trifluoromethylbenzyl bromide.

¹H NMR (DMSO-d₆) δ 4.74 (s, 2 H), 5.68 (s, 2 H), 7.11-7.20 (m, 2 H),7.35-7.39 (m, 2 H), 7.62-7.64 (m, 1 H), 7.64-7.72 (m, 2 H); MS m/e 369(MH⁺).

Compound 104 was prepared according to the same procedure described forcompound 64 and was used immediately upon isolation.

Compound 105 was prepared according to the same procedure described forcompound 16 using 1-(3-aminopropyl)-2-pyrrolidinone instead of3-(methylthio)propylamine.

¹H NMR (CDCl₃) δ 1.93 (m, 2 H), 2.02-2.07 (m, 2 H), 2.39 (t, J=8.05 Hz,2 H), 3.32-3.36 (m, 2H), 3.36-3.45 (m, 4 H), 6.64 (t, J=7.0 Hz, 1 H),6.83 (d, J=8.7 Hz, 1 H), 7.42 (t, J=8.7 Hz, 1 H), 8.07 (bs, 1 H), 8.16(d, J=7.0 Hz, 1 H); MS in/e 263 (MH⁺); Anal. Calcd for C₁₃H₁₇N₃O₃•0.24H2O: C, 58.34; H, 6.58; N, 15.70 Found: C, 58.05; H, 6.20; N, 11.41.

Compound 106 was prepared according to the same reduction proceduredescribed for compound 13.

¹H NMR (CDCl₃) δ 1.83-1.88 (m, 2 H), 1.99-2.05 (m, 2 H), 2.41 (t, J=8.0Hz, 2 H), 3.16 (t, J=6.5 Hz, 2 H), 3.33-3.43 (m, 4 H), 6.63-6.65 (m, 2H), 6.70 (d, J=7.1 Hz, 1 H), 6.78 (t, J=7.5 Hz, 1 H), 7.26 (s, 1 H); MSm/e 233 (MH⁺).

Compound 107 was prepared according to the same procedure described forcompound 14.

¹H NMR (DMSO-d₆) δ 1.87-1.92 (m, 2 H), 1.95-2.00 (m, 2 H), 2.21 (t,J=8.0 Hz, 2 H), 3.25-3.34 (m, 4 H), 4.26 (t, J=7.6 Hz, 2 H), 4.72 (s, 2H), 5.65 (bs, 2 H); MS m/e 273 (MH⁺).

Compound 108 was prepared according to the same procedure described forchloride 2 and was used immediately upon isolation.

A mixture of 2,3-diaminotoluene (10.21 g, 83.57 mmol) and glycolic acid(9.5 3 g, 125.3 6 mmol) in 6 N HCl (1 00 mL) were stirred at I100° C.for 14 hours. The reaction mixture was cooled and made basic (pH 7-8)with ammonium hydroxide. A dark brown solid was collected by filtration,washed with H₂and dried to give 12.47 g (92% yield) of compound 109.

¹H NMR (DMSO-d₆) δ 2.50 (s, 3 H), 4.70 (s, 2 H), 6.93 (d, J=7.3 Hz, 1H), 7.04 (t, J=7.6Hz, 1 H), 7.31 (d, J=7.9Hz, 1 H).

Compound 110 was prepared according to the same procedure described forcompound 24 except that the base employed was cesium carbonate.

¹H NMR (CDCl₃) δ 1.67-1.73 (m, 2 H), 1.89-1.96 (m, 2 H), 2.02 (s, 3 H),2.59 (s, 3 H), 4.05-4.10 (m, 2 H), 4.27 (t, J=7.5 Hz, 2 H), 4.89 (s, 2H), 7.01-7.03 (m, 1 H), 7.12-7.15 (m, 2 H); MS m/e 277 (MH⁺).

Compound 111 was prepared according to the same procedure described forchloride 2 and was used immediately upon isolation. MS m/e 295 (MH⁺).

To a solution of 2-hydroxymethylbenzimidazole (5.92 g, 40.0 mmol) andimidazole (6.81 g, 100.0 mmol) in THF (100 mL) was addedt-butyldimethylsilyl chloride (12.65 g, 84.0 mmol) in several portions.The resulting mixture was stirred at room temperature for 2 hours andfiltered. The filtrate was diluted with EtOAc and washed with H₂O andbrine. The organic layer was dried over MgSO₄ and evaporated. Theresidue was recrystallized from hexanes/EtOAc to give 8.50 g (81%) ofcompound 138 as white needles.

¹H NMR (CDCl₃) δ 0.15-0.16 (m, 6 H), 0.95-0.97 (m, 9 H), 5.02-5.03 (m, 2H), 7.24-7.27 (m, 2 H), 7.59 (bs, 2 H); MS m/e 263 (MH⁺).

Compound 139 was prepared according to the same procedure described forcompound 68 except that cesium carbonate was used instead of sodiumhydride as the base.

¹H NMR (CDCl₃) δ 0.13-0.14 (m, 6 H), 0.91-0.92 (m, 9 H), 2.35-2.37 (m, 2H), 3.58 (t, J=6.0 Hz, 2 H), 4.50 (t, J=7.0 Hz, 2 H), 5.01 (s, 2 H),7.26-7.32 (m, 2 H), 7.44 (d, J=8.0 Hz, 1 H), 7.77 (d, J=10.0 Hz, 1 H);MS m/e 339 (MH⁺).

Compound 140 was prepared through the coupling of compound 139 andcyclopropylsulfide according to the same procedure described forcompound 74 except using cesium carbonate instead of sodium hydride asthe base. The cyclopropylsulfide was prepared according to a literatureprocedure by E. Block, A. Schwan, and D. Dixon in Journal of theAmerican Chemical Society, 1992, 114, 3492-3499.

¹H NMR (CDCl₃) δ 0.12-0.13 (m, 6 H), 0.54-0.56 (m, 2 H), 0.84-0.86 (m, 2H), 0.90-0.91 (m,9 H), 1.87-1.92 (m, 1 H), 2.20-2.25 (m,2 H), 2.62 (t,J=7.0 Hz, 2 H), 4.43 (t, J=7.4 Hz, 2 H), 5.00 (s, 2 H), 7.26-7.32 (m,2H), 7.44 (d, J=8.0 Hz, 1 H), 7.77 (d, J=10.0 Hz, 1 H); MS m/e 377 (MH⁺).

Compound 141 was prepared from compound 140 by the same proceduredescribed for compound 18.

¹H NMR (CDCl₃) δ 0.13-0.14 (m, 6 H), 0.91-0.92 (m, 9 H), 1.01-1.03 (m, 2H), 1.23-1.24 (m, 2 H), 2.31-2.34 (m, 1 H), 2.48-2.52 (m, 2 H), 3.07 (t,J=7.2 Hz, 2 H), 4.51 (t, J=7.1 Hz, 2 H), 5.00 (s, 2 H), 7.26-7.32 (m, 2H), 7.44 (d, J=8.0 Hz, 1 H), 7.77 (d, J=10.0 Hz, 1 H); MS m/e 409 (MH⁺).

To solution of compound 141 (27 mg, 0.07 mmol) in THF (0.5 ml) was addedTBAF (1 M THF solution, 0.13 mL, 0.13 mmol) at 0° C. and the mixture wasstirred for 10 minutes. The solvent was evaporated and the residue waspassed through a short plug of silica (CH₂Cl₂/MeOH, 10:1) to give crudecompound 142 which was used immediately upon isolation.

Compound 143 was prepared according to the same procedure described forcompound 2 and was used immediately upon isolation.

II. Preparation of 2-Oxo-imidazopyridines and 2-Oxo-imidazopyrimidines:

Compounds 26-58 and 112-126 are intermediates prepared according to theprocedures depicted in Scheme III.

3,4-Diaminopyridine (30 g, 274.9 mmol), ethyl acetoacetate (53.66 g, 412mmol) and DBU (1 mL) were stirred at reflux in xylene (300 mL) under aDean-Stark trap. After stirring for 3.5 hours, the solvent wasevaporated and the residue was purified by flash chromatography (EtOAc;EtOAc:MeOH =10:1) to give a solid which was recrystallized fromCH₂Cl2/EtOAc to afford 26 (21.45 g, 45% yield) as white crystals.

¹H NMR (CDCl₃) δ 2.19 (s, 3 H), 5.22 (s, 1 H), 5.46 (s, 1 H), 7.19 (d,J=5.4 Hz, 1 H), 8.20 (d, J=5.4 Hz, 1 H), 8.23 (s, 1 H); MS m/e 176(MH⁺).

Compound 26 (1.0 g, 5.71 mmol) in the presence of 10% palladium oncarbon (0.1 g) in MeOH (10 mL) was hydrogenated in a Parr shaker at 40psi for 2 days. The catalyst was removed by filtration and the filtratewas evaporated to give compound 27 as a white solid.

¹H NMR (CDCl₃) δ 1.57 (d, J=7.0 Hz, 6 H), 4.72-4.76 (m, 1 H), 7.19 (d,J=5.8 Hz, 1 H), 8.30 (d, J=5.8 Hz, 1 H), 8.58 (s, 1 H); MS m/e 178(MH⁺).

The same procedure described for compound 26 was carried out using2,3-diaminopyridine to give 28A and 28 B which were separated by flashchromatography (gradient, CH₂Cl₂/acetone,5:1 to 4:1).

Compound 28A

¹H NMR (CD₃OD) δ 2.31 (s, 3 H), 5.40 (s, 1 H), 5.51 (s, 1 H), 7.04 (dd,J=5.2, 7.7 Hz, 1 H), 7.38 (dd, J=1.4, 7.7 Hz, 1 H), 8.09 (dd, J=1.4, 5.2Hz, 1 H); MS m/e 176 (MH⁺).

Compound 28B

¹H NMR (CD₃OD) δ 2.26 (s, 3 H), 5.21 (s, 1 H), 5.38 (s, 1 H), 7.11 (dd,J=5.5, 7.9 Hz, 1 H), 7.40 (dd, J=1.3, 7.9 Hz, 1 H), 8.09 (dd, J=1.3, 5.5Hz, 1 H); MS m/e 176 (MH⁺).

2-Chloro-3-nitropyridine (7.0 g, 50.0 mmol), cyclopropylamine (3.71g, 65mmol) and potassium carbonate (13.82 g, 100 mmol) were stirred in CH₃CN(100 mL) at room temperature overnight and at reflux for an additionalhour. The solid was filtered and the filtrate was evaporated. Water wasadded to the residue and the mixture was extracted with EtOAc. Thecombined extracts were dried over MgSO₄ and filtered. Evaporation of thesolvent gave 29 (8.40 g, 94% yield) as a dark brown solid.

¹H NMR (CD₃OD) δ 0.63-0.69 (m, 2 H), 0.93-0.97 (m, 2 H), 3.01-3.06 (m, 1H), 6.70-6.72 (dd, J=4.5, 8.3 Hz, 1 H), 8.24 (bs, 1 H), 8.42 (dd, J=1.7,8.3 Hz, 1 H), 8.52 (dd, J=1.7, 4.5 Hz, 1 H); MS m/e 180 (MH⁺).

Compound 29 (8.29 g, 46.28 mmol) was reduced with iron using theprocedure described for compound 7. To the crude diamine in THF (50 mL)was added 1 equivalent of carbonyldiimidazole and the mixture wasstirred at room temperature overnight. The solvent was evaporated andthe residue was diluted with CH₂Cl₂; washed with water, dried over MgSO₄and evaporated. The residue was purified by flash chromatography(gradient, EtOAc/hexane, 1:1 to EtOAc/MeOH, 10: 1) to give 30 (1.93 g,24% yield over two steps) as a light orange solid.

¹H NMR (CDCl₃) δ 1.19 (d, J=3.4 Hz, 2 H), 1.20 (s, 2H), 3.01-3.04 (m, 2H), 7.02 (dd, J=5.3, 7.7 Hz, 1 H), 7.32 (dd, J=1.4, 7.7 Hz, 1 H), 8.12(dd, J=1.4 Hz, 5.3 Hz, 1 H), 9.61 (bs, 1 H); MS m/e 176 (MH⁺).

A mixture of 26 (2.0 g, 11.4 mmol), Cs₂CO₃ (5.58 g, 17.1 mmol) andp-methylsulfonylbenzyl chloride (2.34 g, 11.4 mmol) in acetone (50 mL)was stirred at reflux for 2 hours. The solid was removed by filtrationand the filtrate was evaporated. The residue was purified by flashchromatography (gradient, CH₂Cl₂/MeOH, 40:1 to 20:1) to afford 31 ( 3.24g, 83% yield) as a white solid.

¹H NMR (DMSO-d₆) δ 2.18 (s, 3 H), 3.20 (s, 3 H), 5.23 (s, 2 H), 5.26 (s,1 H), 5.45 (d, J=1.2 Hz, 1 H)), 7.21 (d, J=5.3 Hz, 1 H), 7.63 (d, J=8.4Hz, 2 H), 7.92 (d, J=8.4 Hz, 2 H), 8.25 (d, J=5.1 Hz, 1H), 8.41 (s, 1H); MS m/e 344 (MH⁺).

Compound 32 was prepared using the same procedure for compound 31,except that methylsulfonylbenzyl chloride was replaced with methylp-bromomethylbenzoate.

¹H NMR (DMSO-d₆) δ 2.05 (s, 3H), 3.70 (s, 3H), 5.06 (s, 2H), 5.12 (s,1H), 5.32 (d, J=1.4 Hz, 1H), 7.07-7.09 (dd, J=0.45, 5.4 Hz, 1H), 7.37(d, J=8.4 Hz, 2H), 7.80-7.82 (m, 2H), 8.11 (d, J=5.3 Hz, 1H), 8.23 (s,1H); MS m/e 324 (MH⁺).

A solution of 31 (3.24 g, 9.45 mmol) in concentrated HCl (5 ml) and MeOH(50 ml) was stirred at reflux for 2 hours. The solvent was evaporatedand the residue was triturated in hot MeOH to yield 33 (2.80 g, 87%yield) as a white solid as the HCl salt.

¹H NMR (DMSO-d₆) δ 3.18 (s, 3 H), 5.17 (s, 2 H), 7.07 (d, J=5.2 Hz, 1H), 7.58 (d, J=8.0 Hz, 2 H), 7.91 (d, J=8.2 Hz, 2 H), 8.17 (d, J=5.0 Hz,1 H), 8.29 (s, 1 H); MS m/e 304 (MH⁺).

A solution of 32 (1.30 g, 4.02 mmol) in concentrated HCl (10 ml) andMeOH (10 ml) was stirred at reflux for 1 hour. The solution wasneutralized with K₂CO₃ to pH 6, and extracted with EtOAc. The organiclayer was dried and evaporated to dryness. The crude product wastriturated with hot CH₂Cl₂ to yield 34 (0.85 g, 75% yield) as off-whitesolid.

¹H NMR (DMSO-d₆) δ 3.90 (s, 3 H), 5.20 (s, 2 H), 7.13 (d, J=5.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 2 H), 8.00 (d, J=8.2 Hz, 2 H), 8.22 (d, J=5.2 Hz,1 H), 8.31 (s, 1 H); MS m/e 284 (MH⁺).

A solution of 4-methoxy-3-nitro-pyridine (7.71 g, 50 mmol) andcyclopropylamine (7.14g, 125 mmol) in EtOH (20 mL) was stirred at refluxunder a dry-ice trap condenser for 2 hours. The solvent was evaporatedto give 35 as a yellow solid.

¹H NMR (CD₃OD) δ 0.72-0.75 (m, 2 H), 0.99-1.03 (m, 2 H), 2.63-2.68 (m, 1H), 7.19 (d, J=6.2 Hz, 1 H), 8.26 (bs, 1 H), 8.35 (d, J=6.2 Hz, 1 H),9.22 (s, 1 H); IR (KBr, cm¹) 3369, 1613, 1560, 1515, 1406, 1254, 1195,1039, 881, 846, 769, 545; MS m/e 180 (MH⁺).

To a solution of 35 (12.28 g, 68.6 mmol) in anhydrous MeOH (120 mL) wasadded 10% palladium on carbon (3 g) in several portions under nitrogen.The reduction was carried out using a balloon containing hydrogen (1atm) for 16 hours. The catalyst was removed by filtration through a padof Celite and rinsed with MeOH. The filtrate was concentrated to aslurry and Et₂O was added to precipitate the diamine product as a lightyellow solid (10.1 g, 99% yield).

To a slurry of the diamine and polyvinylpyridine (22.0 g) inacetonitrile (70 mL) of a 20% phosgene solution in toluene was addeddropwise (70 mL, 135.4 mmol). After stirring at room temperature for 2hours, the reaction was quenched with water. Polyvinylpyridine wasremoved by filtration and rinsed with MeOH. The filtrate wasconcentrated and Et₂O was added to precipitate product 36 (15.5g, 98%yield) as a light brown solid.

¹H NMR (CD₃OD) δ 0.95-0.98 (m, 2 H), 1.07-1.14 (m, 2 H), 2.91-2.96 (m, 1H), 7.32 (dd, J=0.5, 5.3 Hz, 1 H), 7.18 (s, 1 H), 8.21 (d, J=5.3 Hz, 1H); MS m/e 176 (MH⁺).

2-Oxo-imidazopyridine 39 was prepared using the same procedure describedfor the preparation of 36, except that cyclopropylamine was replacedwith 2 equivalents of trifluoroethylamine hydrochloride anddiisopropylethylamine, and the reaction was carried out in a sealed tubeat 120-130° C. for 2 days.

¹H NMR (CDCl₃) δ 4.02 (q, J=7.9 Hz, 2 H), 6.83 (d, J=5.5 Hz, 1 H), 8.43(d over bs, 2 H), 9.28 (s, 1 H); IR (KBr, cm⁻¹): 3287, 3241, 1629, 1611,1363, 1254, 1150, 1047, 870; MS m/e 222 (MH⁺); Anal. Calcd forC₇H₆F₃N₃O₂: C, 38.02; H, 2.73; N, 19.00 Found: C, 38.00; H, 2.69; N,19.19.

¹H NMR (CD₃OD) δ 4.23 (q, J=9.0 Hz, 2 H), 7.05 (d, J=6.6 Hz, 1 H), 7.74(d, J=1.1 Hz, 1 H), 7.84 (d, J=1.1, 6.6 Hz, 1 H); IR (KBr, cm¹): 3343,3202, 3062, 1625, 1578, 1529, 1257, 1154, 949; MS m/e 192 (MH⁺); Anal.Calcd for C₇H₈F₃N₃•HCl: C, 36.94; H, 3.99; N, 18.46 Found: C, 37.19; H,3.86; N, 18.79.

¹H NMR (DMSO-d₆) δ 4.99 (q, J=9.2 Hz, 2 H), 7.90 (d, J=6.3 Hz, 1 H),8.61 (d, J=6.3 Hz, 1 H), 8.63 (s, 1 H); IR (KBr, cm⁻¹): 3423, 2994,1744, 1517, 1347, 1254, 1263, 1173, 1000, 811; MS m/e 218 (MH⁺).

2-Oxo-imidazopyridine 41 was prepared using the same procedure describedfor compound 36, except that cyclopropylamine was replaced witht-butylamine and the reaction was carried out in a sealed tube at 80° C.This compound was used as a crude intermediate for the couplingreaction.

¹H NMR (CDCl₃) δ 1.54 (s, 9 H), 7.21 (d, J=6.3 Hz, 1 H), 8.17 (d, J=6.3Hz, I H), 9.08 (s, 1 H); MS m/e 196 (MH⁺).

A mixture of 1,2-dihydro-2-oxo-3H-imidazol[4,5-c]pyridine-3-carboxylicacid, 1,1-dimethyl ethyl ester (470 mg, 2.0 mmol) (prepared according tothe procedure described by N. Meanwell et al. in J. Org. Chem. 1995, 60,1565), Cs₂CO₃ (978 mg, 3.0 mmol) and p-methylsulfonylbenzyl chloride(451 mg, 2.2 mmol) in acetone (10 mL) was stirred at reflux for 2 hours.The mixture was filtered and the filtrate was evaporated. The residuewas purified by flash chromatography (gradient, CH₂Cl₂/MeOH, 40:1 to 20:1) to afford 42 (500 mg, 62% yield) as a white solid.

¹H NMR (CDCl₃) δ 1.71 (s, 9 H), 3.04 (s, 3 H), 5.15 (s, 2 H), 6.90 (m, 1H), 7.54 (m, 2 H), 7.93 (m, 2 H), 8.40 (m, 1 H), 9.01 (m, 1 H); MS m/e404 (MH⁺).

A mixture of 42 (260 mg, 0.64 mmol) and 1 N NaOH (3.22 ml) in THF (5 ml)and water (1 ml) was stirred at the ambient temperature overnight. Themixture was diluted with saturated NH₄Cl and extracted with CH₂Cl₂. Thecombined extracts were dried over MgSO₄ and evaporated. The residue wastriturated with EtOAc to produce 43 (180 mg, 93% yield) as a whitesolid.

¹H NMR (DMSO-d₆) δ 3.34 (s, 3 H), 5.16 (s, 2 H), 7.19 (d, J=5.2 Hz, 1H), 7.56 (d, J=8.4Hz, 2 H), 7.89 (d, J=8.4Hz, 2 H), 8.15 (d, J=5.2Hz, 1H), 8.22 (s, 1 H), 11.34 (s, 1 H); MS m/e 304 (MH⁺).

2-Oxo-imidazopyridine 45 was prepared using the same procedure forcompound 43, except that p-methylsulfonylbenzyl chloride was replacedwith cyclopropylmethyl bromide. This compound was used as a crudeintermediate for the coupling reaction.

¹H NMR (CD₃OD) δ 0.44-0.45 (m, 2 H), 0.56-0.58 (m, 2 H), 1.21-1.25 (m, 1H), 1.69 (s, 9 H), 3.79 (d, J=7.1 Hz, 2 H), 7.35 (d, J=5.4Hz, 1 H), 8.34(d, J5.4 Hz, 1 H), 8.84 (s, 1 H); MS m/e 290 (MH⁺).

¹H NMR (CD₃OD) δ 7.54 (d, J=1.2 Hz, 1 H), 8.19 (d, J=1.2 Hz, 1 H), 8.23(s, 1 H), 8.67 (s, 1 H); MS m/e 137 (MH⁺).

To a solution of 3-hydroxy-2-nitropyridine (100 g, 0.71 mol) in acetone(800 mL) was added potassium carbonate (148 g, 1.07 mol) followed bydimethyl sulfate (99 g, 0.79 mol). The reaction mixture was stirredvigorously using a mechanical stirrer and heated to 60° C. for 4.5hours. The mixture was filtered while still warm. The filtrate wasstripped of solvent to give a crude brown solid. The solid was dilutedwith water and extracted with EtOAc. The organic extracts were driedover anhydrous MgSO₄, filtered and evaporated. The residue was purifiedby flash chromatography (CH₂Cl₂/EtOAc, 1:1) to give 46 as a brightyellow solid (81 g, 74% yield).

¹H NMR (CDCl₃) δ 3.98 (s, 3 H), 7.51-7.57 (m, 2 H), 8.10 (dd, J=1.5, 7.5Hz, 1 H); MS m/e 155 (MH⁺).

Compound 47 was obtained from 46 using the same procedure for thepreparation of 35 except that the reaction was carried out with 1.5equivalents of cyclopropylamine in a sealed tube at 120° C. for 2 days.

¹H NMR (CDCl₃) δ 0.67-0.72 (m, 2 H), 0.89-1.00 (m, 2 H), 2.58-2.65 (m, 1H), 7.50 (dd, J=4.0, 8.6 Hz, 1 H), 7.82 (J=8.6 Hz, 1 H), 7.83 (d, J=8.6Hz, 1 H), 7.97 (dd, J=1.4, 4.0 Hz, 1 H); MS m/e 155 (MH⁺).

A solution of 47 (300 mg, 1.67 mmol) in MeOH (25 mL) was agitated underH₂ (10 psi) in the presence of 10% palladium on carbon (60 mg) for 15min. The catalyst was removed by filtration through a pad of Celite. Tothe filtrate was added urea (402 mg, 6.70 mmol), and the mixture wasevaporated. The solid residue was then heated at 170° C. for 16 hours.The resulting black solid was heated in boiling ethanol and filtered.The filtrate was evaporated and the residue was purified by flashchromatography (gradient, straight CH₂Cl₂ to CH₂Cl₂/MeOH, 20:1) to givecompound 48 as a yellow solid (82 mg, 28% yield). ¹H NMR (CDCl₃) δ0.99-1.04 (m, 2 H), 1.12-1.15 (m, 2 H), 2.89-2.93 (m, 1 H), 7.05 (dd,J=5.3, 7.8Hz, 1 H), 7.41 (dd, J=1.3; 7.8Hz, 1 H), 8.05 (d, J=5.3Hz, 1H); MS m/e 176 (MH⁺).

Compound 49 was prepared from 4,5-diaminopyrimidine and urea using thesame procedure described for compound 48.

To a slurry of 49 (136 mg, 1.0 mmol) in THF (5 mL) was added BTPP (946mg, 3.0 mmol) and p-methylsulfonylbenzyl chloride (205 mg, 1.0 mmol) atambient temperature. After stirring overnight, the solution was dilutedwith EtOAc, washed with water, dried over MgSO₄ and evaporated. Theresidue was purified by flash chromatography (gradient, CH₂Cl₂/MeOH,40:1 to 20:1) to afford compound 50 (52 mg, 34% yield) as a white solid.

¹H NMR (CD₃OD) δ 3.08 (s, 3 H), 5.26 (s, 2 H), 7.67 (d, J=8.4 Hz, 2 H),7.91-7.93 (m, 2 H), 8.34 (s, 1 H), 8.74 (s, 1 H); MS m/e 305 (MH⁺).

To a suspension of 4,6-dichloro-5-nitropyrimidine (3.88 g, 20.0 mmol)and triethylamine (4.05 g, 40.0 mmol) in THF (50 ml) was addedcyclopropylamine (1.14 g, 20.0 mmol) dropwise at 0° C. After stirring at0° C. for 2 hours, the slurry was filtered. The filtrate was dilutedwith EtOAc, washed with water, dried over MgSO₄, and evaporated. Theresidue was purified by flash chromatography (gradient, CH₂Cl₂/MeOH,100:1 to 40:1) to afford compound 51 (2.75 g, 64% yield) as a yellowsolid.

¹H NMR (DMSO-d₆) δ 0.61-0.64 (m, 2 H), 0.74-0.78 (m, 2 H), 2.92 (bs, 1H), 8.43 (bs, 1 H), 8.51 (s, 1 H); MS m/e 215 (MH⁺).

Pyrimidine 51 was reduced using catalytic hydrogenation with 10%palladium on carbon in MeOH at 40 psi (Parr shaker) for 1 hour to affordcompound 52.

¹H NMR (DMSO-d₆) δ 0.74-0.76 (m, 2 H), 0.79-0.83 (m, 2 H), 3.06-3.11 (m,1 H), 6.17 (bs, 2 H), 7.47 (d, J=1.5 Hz, 1 H), 8.37 (d, J=1.0 Hz, 1 H),9.09 (d, J 3.8 Hz, 1 H); MS m/e 151 (MH⁺).

Compound 53 was obtained by cyclization of diamine 52 according to thesame procedure described for compound 36 using phosgene andpolyvinylpyridine.

¹H NMR (CD₃OD) δ 1.14-1.19 (m, 2 H), 1.20-1.27 (m, 2 H), 3.11-3.18 (m, 1H), 8.47 (d, J=0.45 Hz, 1 H), 9.01 (s, 1 H); MS m/e 177 (MH⁺).

2-Oxo-imidazopyrimidine 56 was prepared using the same procedure forcompound 53, except that cyclopropylamine was replaced witht-butylamine. The compound was used as a crude intermediate for thecoupling reaction without further purification.

¹H NMR (CDCl₃) δ 1.52 (s, 9 H), 7.26 (bs, 1 H), 8.37 (s, 1 H); MS m/e231 (MH⁺).

¹H NMR (CD₃OD) δ 1.57 (s, 9 H), 7.49 (d, J=1.3 Hz, 1 H), 8.27 (d, J=1.3Hz, 1 H); MS m/e 167 (MH⁺).

2-Oxo-imidazopyrimidine 58 was prepared according to the same proceduredescribed for compound 53, except that cyclopropylamine was replacedwith 2,2,2-trifluoroethylamine. The crude intermediate was used in thecoupling reaction without further purification.

¹H NMR (CD₃OD) δ 4.30-4.36 (m, 2 H), 8.46 (s, 1 H); MS m/e 226 (MH⁺).

2-Oxo-imidazopyridine 113 was prepared according to the same procedurefor the preparation of 36, except that cyclopropylamine was replacedwith 2 equivalents of 3-amino-5-methylisoxazole, and the reaction wascarried out in MeOH at 100° C. for 18 hours in a sealed pressure tube.

¹H NMR (CD₃OD) δ 0.88 (s, 3 H), 4.71 (s, 1 H), 6.79 (d, J=6.2 Hz, 1 H),6.95 (d, J=6.2 Hz, 1 H), 7.69 (d, 1 H); IR (KBr, cm⁻¹) 3323, 3125, 3097,1604, 1581, 1521, 1499, 1228, 1179; MS m/e 221 (MH⁺); Anal. Calcd forC₉H₈N₄O₃: C, 49.09; H, 3.66; N, 25.44 Found: C, 49.04; H, 3.63; N,25.06.

¹H NMR (CD₃OD) δ 2.50 (s, 3 H), 6.94 (s, 1 H), 7.95 (dd, J=0.6, 6.55 Hz,1 H), 8.31 (s, 1 H), 8.32 (d, J5.5 Hz, 1 H); IR (KBr, cm⁻¹) 3546, 3463,2679, 1744, 1720, 1596, 1474, 1457, 1193, 1129, 809, 633; MS m/e 217(MH⁺).

A mixture of compound 26 (400 mg, 2.28 mmol) and BTPP (1.57 g, 5.02mmol) in THF (10 mL) was stirred for 20 minutes after which2,2,2-trifluoroethyl p-toluenesulfonate (605 mg, 2.40 mmol) was added tothe mixture. The reaction mixture was stirred at 45° C. for 18 hours andthen at 60° C. for an additional 24 hours. The solvent was evaporatedand the residue was diluted with H₂O and extracted with EtOAc. Thecombined organic extracts were dried over MgSO₄ and evaporated.Purification by flash column chromatography (EtOAc/MeOH, 20:1) gave 295mg (50% yield) of 114 as a white solid.

¹H NMR (CDCl₃) δ 2.24 (s, 3 H), 4.51 (q, J=8.6 Hz, 2 H), 5.24 (s, 1 H),5.43 (d, J=1.1 Hz, 1 H), 7.10 (d, J=5.5Hz, 1 H), 8.39 (s, 1 H), 8.40 (d,J=5.5 Hz, 1 H); IR(KBr,cm¹)3026, 1727, 1605, 1503, 1169, 1156, 1126,827; MS m/e 258 (MW+).

Compound 114 (272 mg, 1.06 mmol) and concentrated HCl (12 mL) in MeOH(20 mL) were refluxed for 72 hours. The solvent was evaporated and theresidue was dried under vacuum to give 263 mg (99% yield) of compound115 as the HCl salt.

¹H NMR (DMSO-d₆) δ 4.93 (q, J=9.2 Hz, 2 H), 7.61 (d, J=6.3 Hz, 1 H),8.54 (d, J=6.3 Hz, 1 H), 8.89 (s, 1 H); MS m/e 218 (MH⁺).

Compound 28B (1.2 g, 6.86 mmol) and BTPP (3.21 g, 10.28 mmol) in CH₂Cl₂were mixed together in a sealed flask and cooled to -78° C.Chlorodifluoromethane (gas, approximately 2 g, 23.26 mmol) was bubbledinto the solution in the sealed flask. The flask was sealed and thetemperature was raised to 0° C. for 10 minutes and then to roomtemperature for 3 minutes. The reaction mixture was diluted with H₂O andextracted with CH₂Cl₂. The combined extracts were dried over MgSO₄ andevaporated. To the residue was added 6 N HCl in MeOH (1 :1 mixture, 10mL). The mixture was stirred at reflux for 6 hours. The reaction wasneutralized with solid Na₂CO₃. The solvent was concentrated and theresulting aqueous solution was extracted with CH₂Cl₂. The combinedextracts were dried over MgSO₄ and evaporated. Purification by flashcolumn chromatography (gradient, straight EtOAc to EtOAc/MeOH, 5:1) gave398 mg (31% yield) of 116.

¹H NMR (CDCl₃) δ 7.14 (dd, J=5.7, 7.4 Hz, 1 H), 7.36 (t, J=58.7 Hz, 1H), 7.62 (d, J=7.8 Hz, 1 H), 8.21 (d, J=5.3 Hz, 1 H), 9.40 (bs, 1 H); MSm/e 186 (MH⁺).

Compound 119 was prepared using the same procedure described for thepreparation of 36, except that cyclopropylamine was replaced with 2equivalents of cyclopentylamine, and the reaction was carried out in asealed pressure tube at 120° C. for 2 hours.

¹H NMR (CDCl₃) δ 1.62-1.69 (m, 2 H), 1.70-1.76 (m, 2 H), 1.79-1.85 (m, 2H), 2.10-2.16 (m, 2 H), 3.96-4.01 (m, 1 H), 6.76 (d, J=6.2 Hz, 1 H),8.23 (bs, 1 H), 8.27 (d, J=6.2 Hz, 1 H), 9.21 (s, 1 H); MS m/e 208(MH⁺).

¹H NMR (CDCl₃) δ 1.48-1.53 (m, 2 H), 1.61-1.64 (m, 2 H), 1.69-1.74 (m, 2H), 2.00-2.06 (m, 2 H), 3.12 (bs, 2 H), 3.77-3.83 (m, 1 H), 4.22 (bd,J=4.5 Hz, 1 H), 6.47 (d, J=5.4 Hz, 1 H), 7.85 (s, 1 H), 7.92 (d, J=5.4Hz, 1 H); MS m/e 178 (MH⁺).

¹H NMR (DMSO-d₆) δ 1.61-1.68 (m, 2 H), 1.85-1.95 (m, 4 H), 1.97-2.02 (m,2 H), 4.11 (bs, 1 H), 4.67-4.74 (m, 1 H), 7.20 (d, J=5.3 Hz, 1 H), 8.16(d, J=5.4 Hz, 1 H), 8.19 (s, 1 H); MS m/e 204 (MH⁺).

Compound 122 was prepared using the same procedure described for thepreparation of 36, except that cyclopropylamine was replaced with 2equivalents of cyclobutylamine, and the reaction was carried out in asealed pressure tube at 100° C.

¹H NMR (CDCl₃) δ 1.89-1.97 (m, 2 H), 2.05-2.09 (m, 2 H), 2.50-2.56 (m, 2H), 4.06-4.13 (m, 1 H), 6.56-6.62 (m, 1 H), 8.23 (s, 1 H), 8.27 (d,J=5.6 Hz, 1 H), 9,21 (s, 1 H); MS m/C 194 (MH⁺).

¹H NMR (DMSO-d₆) δ 1.70-1.79 (m, 2 H), 1.83-1.91 (m, 2 H), 2.32-2.50 (m,2 H), 3.85-3.91 (m, 1 H), 4.59 (s, 2 H), 5.49 (d, J=6.2 Hz, 1H), 6.22(d, J=5.3 Hz, 1 H), 7.55 (d, J=5.2 Hz, 1 H), 7.63 (s, 1 H); MS m/e 164(MH⁺).

¹H NMR (CD₃OD) δ 1.92-2.04 (m, 2 H), 2.43-2.49 (m, 2 H), 2.88-2.97 (m, 2H), 4.93-4.98 (m, 1 H), 7.83 (d, J=6.6 Hz, 1 H), 8.41-8.43 (m, 2 H); MSm/e 190 (MH⁺).

To a solution of 4-chloro-3-nitropyridine (4.9 g, 30.80 mmol) and2-(3-aminopropyl)-2-pyrrolidinone (4.4 g, 30.80 mmol) in CH₃CN (50 mL)was added K₂CO₃ (4.25 g, 30.8 mmol) and the mixture was stirred for 8hours. Additional 1-(3-aminopropyl)-2-pyrrolidinone (0.2 g, 1.41 mmol)was added and the mixture was stirred for 24 hours at room temperature.The mixture was filtered and concentrated to give 8.0 g (98% yield) ofthe compound 123 as an orange oil.

¹H NMR (CDCl₃) δ 1.89-1.99 (m, 2 H); 2.02-2.15 (m, 2 H), 2.35 (t, J=8.05Hz, 2 H); 3.36-3.47 (m, 6 H), 6.70 (d, J=6.2 Hz, 1 H), 8.28 (d, J=6.27Hz, 1 H), 8.37-8.40 (s, 1 H), 9.20 (s, 1 H); MS m/e 264 (MH⁺).

A mixture of 123 (2.0 g, 7.6 mmol) and 10% palladium on carbon (200 mg)in EtOH (50 mL) was hydrogenated at 50 psi for 18 hours, filtered andconcentrated to give 1.6 g (90% yield) of the diamine as a black oil.The oil was dissolved in CH₂Cl₂ (40 mL), treated with carbonyldiimidazole (1.22 mg, 7.5 mmol) and stirred for 12 hours at roomtemperature. The solvent was evaporated and the residue was subjected toflash column chromatography (gradient, 3% MeOH/CH₂Cl₂ to 10%MeOH/CH₂Cl₂) to give 1.09 g (62% yield) of compound 124 as an orangegum.

¹H NMR (CDCl₃) 5 2.01-2.05 (m, 4 H), 2.39 (t, J=7.9 Hz, 2 H) 3.37-3.43(m, 4 H), 3.90 (t, J=7.2 Hz, 2 H), 7.01 (d, J=5.4 Hz, 1 H), 8.29 (d,J=5.4 Hz, 1 H), 8.37 (s, 1 H); MS m/e 260 (MH⁺).

A mixture of 28A (1.00 g, 5.71 mmol), o-fluoronitrobenzene (0.88 g, 6.28mmol) and Cs₂CO₃ (5.58 g, 17.1 mmol) in DMF was stirred at roomtemperature for 12 hours. The reaction mixture was diluted with EtOAcand washed with water and brine, dried over MgSO₄, and concentrated.Purification by flash chromatography (gradient, CH₂Cl₂/hexane, 40:1 to20:1) gave 1.10 g (65% yield) of 125 as a yellow foam.

¹H NMR (CDCl₃) δ 2.28-2.32 (m, 3 H), 5.45-5.49 (m, 2 H), 7.01-7.05 (m, 1H), 7.11-7.15 (m, 1 H), 7.62-7.68 (m, 2 H), 7.80-7.84 (m, 1 H),8.14-8.22 (m, 2 H); MS m/e 297 (MH⁺).

Compound 126 was prepared from compound 125 according to the sameprocedure described for compound 115.

¹H NMR (DMSO-d₆) δ 7.06-7.09 (m, 1 H), 7.33-7.34 (m, 1 H), 7.75-7.79 (m,1 H), 7.85-7.87 (m, 1 H), 7.94-7.98 (m, 1 H), 8.04-8.05 (m, 1 H),8.21-8.23 (m, I H); MS m/e 257 (MH⁺).

III. Preparation of R₁-LGs:

Compound 127 was prepared according to the procedure described by A.Yebga et al. in Eur. J Med. Chem., 1995, 30, 769-777.

Compound 128 was prepared according to the procedure described by J. C.Heslin and C. J. Moody in J. Chem. Soc. Perkins Trans. I, 1988, 6,1417-1423.

Compound 129 was prepared according to the same procedure described forcompound 127.

¹H NMR (CDCl₃) δ 1.22 (s, 6 H), 1.57-1.60 (m, 2 H), 1.92-1.98 (m, 3 H),3.42 (t, J=6.7 Hz, 2 H).

To neat 2,6-lutidine (11.42 g, 106.60 mmol) cooled with an ice bath to0° C. was added t-butyldimethylsilyltrifluoromethane sulfonate (16.91 g,63.96 mmol). After 30 minutes, a solution of compound 129 (7.72 g, 42.64mmol) in CH₂Cl₂ (15 mL) was added. The resulting brown reaction mixturewas stirred at 0° C. for 2.5 hours. The reaction mixture was poured ontoice (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL)and extracted with CH₂Cl₂. The combined organic extracts were dried overMgSO₄ and evaporated. The crude brown oil was purified by flash columnchromatography (pentane:Et₂O, 15:1) to give compound 130 as a colorlessoil.

¹H NMR (CDCl₃) δ 0.07 (s, 6 H), 0.85 (s, 9 H), 1.21 (s, 6 H), 1.52-1.55(m, 2 H), 1.93-1.99 (m, 2 H), 3.42 (t, J=6.7 Hz, 2 H).

Compound 131 was prepared according to the procedure described by OKulinkovich et al. in Tetrahedron Letters, 1996, 37, 1095-1096. To asolution of ethyl-4-bromobutyrate (16.36 g, 83.85 mmol) in Et₂O (200 mL)was added titanium (IV) isopropoxide (2.38 g, 8.39 mmol). Ethylmagnesiumbromide (3.0 M in Et₂O, 58.7 mL, 176.09 mmol) was added to the mixtureslowly via addition funnel over 30 minutes maintaining the temperaturebetween 10-20° C. The reaction mixture was stirred for 6 hours at roomtemperature and then poured slowly into chilled 10% aqueous H₂SO₄ (300mL) and stirred. The layers were separated and the aqueous layer wasfurther extracted with Et₂O. The combined organic extracts were driedover MgSO₄ and evaporated. The crude oil was purified by flash columnchromatography (gradient, hexanes/Et₂O 3:1 to 1:1) to give 10.3g (67%yield) of compound 131 as a yellow oil.

¹H NMR (CDCl₃) δ 0.42-0.48 (m, 2 H), 0.69-0.76 (m, 2 H), 1.63-1.70 (m, 2H), 2.05-2.14 (m, 2 H), 3.45-3.50 (m, 2 H);

Compound 132 was prepared from compound 131 according to the sameprocedure described for compound 130 and was used immediately forcoupling upon isolation.

Compound 133 was prepared according to the same procedure described forcompound 131 using ethyl 3-bromopropionate.

¹H NMR (CDCl₃) 60.51 (t, J=6.1 Hz, 2 H), 0.76 (t, J=6.2Hz, 2 H), 2.07(t, J=7.3 Hz, 2 H), 3.57 (t, J=7.3 Hz, 2 H).

Compound 134 was prepared from compound 133 according to the sameprocedure described for compound 130.

¹H NMR (CDCl₃) δ 0.10 (s, 6 H), 0.50 (t, J=6.3 Hz, 2 H), 0.74 (t, J=6.3Hz, 2 H), 0.85 (s, 9 H), 2.03 (t, J=8.0 Hz, 2 H), 3.56 (t, J=8.0 Hz, 2H).

A solution of 4-(trifluoromethylthio) benzoic acid (5.00 g, 22.50 mmol)and triethylamine (2.36g, 23.40 mmol) in THF (50 mL) was cooled to 0° C.and to the solution was added ethyl chloroformate (2.53 g, 23.40 mmol).The mixture was filtered and the added dropwise to a cooled solution ofsodium borohydride (3.54 g, 93.38 mmol) in a mixture of H₂O and THF (1:1 ratio, 50 mL). The reaction mixture was stirred for 2 hours keepingthe temperature below 15° C. and then for 18 hours at room temperature.The reaction was quenched with IN HCl and the organic layer wasseparated. The aqueous layer was extracted with Et₂O and all organiclayers were combined, dried over Na₂SO₄, and evaporated. The resultingsolid was dissolved in EtOAc and was washed with saturated aqueousNaHCO₃. The organic layer was dried over Na₂SO₄ and evaporated to give3.53 g (75% yield) of compound 135 as a white solid.

¹H NMR (DMSO-d₆) δ 4.57 (d, J=5.7 Hz, 2 H), 5.38 (t, J=5.7 Hz, 1 H),7.48 (d, J=7.3 Hz, 2 H), 7.68 (d, J=7.3 Hz, 1 H).

A mixture of compound 135 (3.50 g, 16.81 mmol), hydrogen peroxide (30%,19.05 g, 168.10 mmol) and glacial acetic acid (40 mL) was stirred at 80°C for several minutes and then at 50° C. for 48 hours. The solution waspoured into H₂O and extracted with Et₂O. The combined extracts werewashed with aqueous 10% NaHCO₃, dried over Na₂SO₂, and evaporated togive 3.6 g (89% yield) of compound 136 as a white solid.

¹H NMR (DMSO-d₆) δ 4.70 (d, J=7.1 Hz, 2 H), 5.61 (bs, 1 H), 7.78 (d,J=7.2 Hz, 2 H), 8.10 (d, J=7.2 Hz, 2 H).

A solution of alcohol 136 (2.0 g, 8.32 mmol) in Et₂O (50 mL) was cooledto −5° C. with an ice/salt bath. To this solution was added phosphoroustribromide and the resulting mixture was stirred at −5° C. for 5 hoursand then at room temperature for 18 hours. The reaction mixture waspoured into ice water and the aqueous layer was extracted with Et₂O. Thecombined organic layers were washed with saturated aqueous NaHCO₃,saturated aqueous NaCl, dried over Na₂SO₄, and evaporated to give 1.45 g(56% yield) of 137 as a clear oil.

¹H NMR (DMSO-d₆) δ 4.87 (s, 2 H), 7.91 (d, J=8.5 Hz, 2 H), 8.15 (d,J=8.4 Hz,2H).

IV. Preparation of Examples of Formula I:

Unless a specific procedure is described, Examples 1-166 are preparedaccording to the general coupling procedures described below:

General Coupling Procedure of 2-Chloromethyl-benzimidazoles (II) and2-Oxo-imidazopyridines or 2-Oxo-imidazopyrimidines in Scheme I-A.

Examples 1-3, 8-12, 14-16, 23-46, 65, 69-70, 72, 90, 94, 102, 104,111-113, 120, 122, 126, 128-131, 135-136, 140-151, 156-157, 154-155, 157and 160-163, and 166 were prepared according to the following procedure:

To a solution of II and 2-oxo-imidazopyridine or 2-oxo-imidazopyrimidine(1 equivalent of each) in THF or CH₂Cl₂ or DMF is added 3-4 equivalentsof BTPP or Cs₂CO₃. The mixture is stirred at 0° C. or room temperaturefor 1-16 hours. The solvent is evaporated, and the residue is dilutedwith water and extracted with EtOAc. The crude product is then purifiedby chromatography on silica gel or by reverse phase preparative HPLC.

General Procedure of Reacting Ia with R₂-LG in Scheme I-B.

Examples 5-7, 18, 100, and 138 were prepared according to the followingprocedure:

To a solution of Ia and 1.5-3 equivalents of BTPP, Cs₂CO₃, or BEMP onpolystyrene resin in THF or DMF is slowly added R₂-LG at roomtemperature. When the reaction is completed, the solvent is evaporatedor resin is filtered and filtrate is evaporated. The residue is purifiedby dissolving in EtOAc or CH₂Cl₂ and washing with water followed byflash chromatography, or by trituration of the solid collected from thereaction in solvents such as MeOH, or by reverse phase preparative HPLC.

General Procedure of Reacting V with R₁-LG in Scheme I-C.

Examples 48, 67-68, 76, 78, 80, 82, 84, 88, 124, and 152-153 wereprepared according to the following procedure.

To a mixture of V and 1.5-3 equivalents of sodium hydride or BEMP onpolystryrene resin in THF, DMF or CH₃CN is added R₁-LG. The reaction isstirred at temperatures ranging from 0° C. to 80° C. for 30 minutes to18 hours In examples where BEMP on polystyrene resin is utilized, theresin is filtered. The filtrate is evaporated and the residue ispurified by flash column chromatography on silica or reverse phasepreparative HPLC. In examples where sodium hydride is used as base, thereaction mixture is diluted with water, extracted with EtOAc or CH₂Cl₂,and purified by flash column chromatography on silica or reverse phasepreparative HPLC.

EXAMPLE 1

¹H NMR (CDCl₃) δ 2.05-2.11 (m, 2 H), 2.29 (s, 3 H), 2.50 (t, J=7.1 Hz, 2H), 4.58 (t, J=7.6 Hz, 2 H), 5.36 (s, 1 H), 5.48 (s, 3 H), 7.06 (dd,J=5.2, 7.8 Hz, 1 H), 7.35-7.45 (m, 3 H), 7.84 (d, J=7.4 Hz, 1 H), 7.94(bd, J=6.4 Hz, 1 H), 8.08 (dd, J=1.2, 5.2 Hz, 1 H); IR (KBr, cm¹) 3423,2952, 2243, 1698, 1656, 1618, 1452, 1403, 1336, 1247, 1152, 790, 766,743; MS m/e 373 (MH⁺); Anal. Calcd for C₂₁H₂₀N₆0: C, 67.73; H, 5.41; N,22.57 Found: C, 67.35; H, 5.35; N, 22.41.

EXAMPLE 2

¹H NMR (CDCl₃) δ 1.13-1.21 (m, 4 H), 2.06-2.12 (m, 2 H), 2.51 (,J=7.2Hz, 2 H), 3.01-3.05 (m, 1 H), 4.57 (,J=7.5 Hz, 2 H), 5.42 (s, 2 H),7.01-7.05 (m, 1 H), 7.3 4-7.47 (m, 3 H), 7.81-7.86 (m, 2 H), 8. 10 (d,J=4.8 Hz, 1 H); IR (KBr, cm⁻¹) 3424, 2244, 1702, 1333, 1474, 1461, 1280,1164, 789; MS m/e 373 (MH⁺).

EXAMPLE 3

¹H NMR (CD₃OD) δ 1.68 (s, 9 H), 2.18-2.21 (m, 2 H), 2.60 (t, J=7.2 Hz, 2H), 4.50 (t, J=7.6 Hz, 2 H), 5.48 (s, 2 H), 7.23-7.25 (m, 1 H), 7.30 (t,J=7.2 Hz, I H), 7.35 (d, J=5.4 Hz, 1 H), 7.54 (d, J=8.0 Hz, 1 H), 7.56(d, J=8.0 Hz, 1 H), 8.31 (d, J=5.4 Hz, 1 H), 8.88 (s, 1 H); MS m/e 433(MH⁺).

EXAMPLE 4

The t-butoxycarbonyl group of Example 4 was removed by treating withaqueous 1 N NaOH solution using the procedure described for thepreparation of intermediate compound 43.

¹H NMR (CD₃OD) 62.05-2.11 (m, 2 H), 2.63 (t, J=7.4Hz, 2 H), 4.41 (t,J=7.5 Hz, 2 H), 5.39 (s, 2 H), 7.16-7.19 (m, 1 H), 7.24-7.27 (m, 2 H),7.55 (d, J=8.0 Hz, 1 H), 7.61 (d, J=8.0 Hz, 1 H), 8.17 (d, J=5.2 Hz, 1H), 8.25 (s, 1 H), 11.34 (s, 1 H); MS m/e 333 (MH⁺).

EXAMPLE 5

¹H NMR (DMSO-d₆) δ 2.14-2.17 (m, 2 H), 2.65 (t, J=7.4 Hz, 2 H), 4.41 (t,J 7.5 Hz, 2 H), 5.52 (s, 2 H), 7.18 (t, J=8.0Hz, 1 H), 7.28 (t, J=8.0Hz, 1 H), 7.51 (d, J=5.3 Hz, 1 H), 7.55 (d, J=8.0 Hz, 1 H), 7.64 (d,J=8.2 Hz, 1 H), 8.47 (d, J =5.3 Hz, 1 H), 8.65 (s, 1 H); IR (KBr, cm¹)3436, 2987, 2263, 1760, 1608, 1384, 1125, 748; MS m/e 358 (MH⁺); Anal.Calcd for C₁₉H₁₅N₇O•0.6EtOAc: C, 62.65; H, 4.87; N, 23.90 Found: C,62.33; H, 4.76; N, 24.14.

EXAMPLE 6

¹H NMR (CD₃OD) 5 1.53 (d, J=6.8 Hz, 6 H), 2.27-2.32 (m, 2 H), 2.65 (t,J=7.2 Hz, 2 H), 4.08-4.12 (m, 1 H), 4.57 (t, J=7.5 Hz, 2 H), 5.68 (s, 2H), 7.30 (t, J=7.3 Hz, 1 H), 7.39 (t, J=7.2 Hz, 1 H), 7.56 (d, J=8.0 Hz,1 H), 7.67 (d, J=8.2 Hz, 1 H), 7.88 (d, J=6.3 Hz, 2 H), 8.61 (d, J=6.3Hz, 1 H), 8.94 (s, 1 H); IR (KBr, cm⁻¹) 3420, 2314, 2251, 2075, 2008,1752, 1623, 1509, 1369, 1180, 738; HRMS m/e 439.1552 (MH⁺).

EXAMPLE 7

¹H NMR (DMSO-d₆) δ 2.11-2.12 (m, 2 H), 2.63 (t, J=7.4 Hz, 2 H), 4.42 (t,J=7.4 Hz, 2 H), 5.28 (s, 2 H), 5.50 (s, 2 H), 7.18 (t, J=8.0 Hz, 1 H),7.26 (t, J=8.0 Hz, 1 H), 7.35 (d, J=5.3 Hz, 1 H), 7.55-7.57 (m, 3 H),7.62 (d, J=8.1 Hz, 1 H), 7.86 (d, J=8.2 Hz), 8.24 (d, J=5.2 Hz, 1H),8.40 (s, 1 H); IR (KBr, cm⁻¹) 3424, 2953, 2250, 2229, 1716, 1609, 1503,825, 744; MS m/e 448 (MH⁺); Anal. Calcd for C₂₆H₂₁N₇O•90.25H₂O: C,69.09; H, 4.79; N, 21.69 Found: C, 69.00; H, 4.81; N, 21.77.

EXAMPLE 8

¹H NMR (DMSO-d₆) δ 2.10-2.13 (m, 2 H), 2.64 (t, J=7.4 Hz, 2 H), 3.20 (s,3 H), 4.43 (t, J=7.4Hz, 2 H), 5.30 (s, 2 H), 5.51 (s, 2 H), 7.19 (t,J=8.0Hz, 1 H), 7.27 (t, J=7.2 Hz, 1 H), 7.35 (d, J=5.2 Hz, 1 H), 7.55(d, J=8.0 Hz, 1 H), 7.62-7.65 (m, 3 H), 7.93 (d, J=8.3 Hz, 2 H), 8.24(d, J=5.2 Hz, 1 H), 8.43 (s, 1 H); IR (KBr, cm⁻¹) 3424, 2246, 1707,1614, 1501, 1407, 1306, 1148; MS m/e 501 (MH⁺); Anal. Calcd forC₂₆H₂₄N₆O₃S: C, 62.38; H, 4.83; N, 16.78 Found: C, 62.31; H, 4.73; N,16.75.

EXAMPLE 9

¹H NMR (DMSO-d₆) δ 2.11-2.14 (m, 2 H), 2.65 (t, J=7.4 Hz, 2 H), 3.21 (s,3 H), 4.44 (t,J=7.4 Hz, 2 H), 5.30 (s, 2 H), 5.51 (s, 2 H), 7.16 (m, 1H), 7.36 (d, J=5.2 Hz, 1 H), 7.40 (q, J=2.4, 9.7 Hz, 1 H), 7.63-7.68 (m,3 H), 7.94 (d, J=8.4 Hz, 2 H), 8.25 (d, J=5.2 Hz, 1 H), 8.44 (s, 1 H);IR (KBr, cm⁻¹) 3423, 2926, 2248, 1707, 1613, 1602, 1148; MS m/e 519(MH⁺); Anal. Calcd for C₂₆H₂₃FN₆O₃S: C, 60.22; H, 4.47, N, 16.20 FoundC, 60.06; H, 4.69, N, 16.21.

EXAMPLE 10

¹H NMR (DMSO-d₆) δ 2.09-2.13 (m, 2 H), 2.64 (t, J=7.4 Hz, 2 H), 3.84 (s,3 H), 4.43 (t, J=7.4 Hz, 2 H), 5.26 (s, 2 H), 5.50 (s, 2 H), 7.13-7.17(m, 1 H), 7.34-7.40 (m, 2 H), 7.51 (d, J=8.3 Hz, 2 H), 7.64-7.67 (m, 1H), 7.96-7.97 (m, 2 H), 8.23 (d, J=5.2 Hz, 1 H), 8.39 (s, 1H); IR (KBr,cm⁻¹) 3432, 2954, 2245, 1719, 1698, 1499, 1284, 1139; MS m/e 499 (MH⁺);Anal. Calcd for C₂₁H₂₃FN₆O₃: C, 65.05; H, 4.65; N, 16.85 Found: C,65.25; H, 4.65; N, 16.87.

EXAMPLE 11

¹H NMR (DMSO-d₆) δ 2.17-2.23 (m, 2 H), 3.02 (s, 3 H), 3.20 (s, 3H), 3.26(t, J=8.0 Hz, 2 H), 4.51 (t, J=7.7 Hz, 2 H), 5.29 (s, 2 H), 5.50 (s, 2H), 7.16 (dt, J=2.4, 9.2 Hz, 1 H), 7.3 6 (d, J=4.9 Hz, 1 H), 7.40 (dd,J=2.4, 9.5 Hz, 1 H), 7.63 (d, J=8.2 Hz, 2 H), 7.68 (dd, J=4.9, 8.9 Hz, 1H), 7.93 (d, J=8.3 Hz, 2 H), 8.25 (d, J=5.2 Hz, 1 H), 8.43 (s, 1 H); IR(KBr, cm⁻¹) 3442, 2925, 2360, 1712, 1614, 31500, 1490, 1296, 147, 761,530; MS m/e 572 (MH⁺); Anal. Calcd for C₂₆H₂₆FN₅O₅S₂: C, 54.62; H, 4.58; N, 12.2 5 Found: C, 54.48; H, 4.69; N, 12.14.

EXAMPLE 12

¹H NMR (CDCl₃) δ 0.98 (s, 3 H), 0.95 (s, 3 H), 1.44-1.52 (m, 2 H),1.60-1.73 (m, 1 H), 2.25 (s, 3 H), 4.28-4.33 (m, 2 H), 5.20 (s, 1 H),5.41 (s, 3 H), 7.02 (d, J=5.1 hz, 1 H), 7.27-7.31 (m, 3 H), 7.77-7.80(m, 1 H), 8.31 (d, J=5.1 Hz, 1 H), 8.73 (s, 1 H); MS m/e 376 (MH⁺); IR(KBr, cm⁻¹) 2957, 1712, 1603, 1494, 1398, 1330, 1167, 1138, 816, 740;Anal. Calcd for C₂₂H₂₅N₅O: C, 70.38; H, 6.71; N, 18.65 Found: C, 70.24;H, 6.67; N, 18.71.

EXAMPLE 13

To a solution of 4-chloro-1-methyl-1,3-dihydro-imidazo[4,5c]pyridin-2-one (Salor of Aldrich Chemical, 100 mg, 0.55 mmol) in DMF(10 mL) was added sodium hydride (26 mg, 60% dispersion in mineral oil)at room temperature. After stirring for 30 min, a neutral form ofcompound 4 (155 mg, 0.654 mmol) was added. The resulting mixture wasstirred overnight and evaporated. The residue was diluted with water andextracted with Et₂O. The combined extracts were dried over MgSO₄ andevaporated. The residue was purified by flash chromatography (gradient,EtOAc, then EtOAc/MeOH, 20:1 to 10:1) to give the Example 13 (78 mg, 38%yield).

¹H NMR (CDCl₃) δ 1.07 (d, J=6.3 Hz, 6 H), 1.72-1.86 (m, 3 H), 3.52 (s, 3H), 4.27 (t, J=7.7 Hz, 2 H), 5.64 (s, 2 H), 6.98 (d, J=5.3 Hz, 1 H),7.18-7.30 (m, 2 H), 7.35 (d, J=7.5 Hz, 1 H), 7.66 (d, J=7.4 Hz, 1 H),8.13 (d, J=5.3 Hz, 1 H); IR (KBr, cm) 3449, 2954, 1735, 1613, 1586,1503, 1441, 1133, 775; MS m/e 384 (MH⁺); Anal. Calcd forC₂₀H₂₂ClN₅O•1.10 H₂O: C, 59.50; H, 6.04; N, 17.35 Found: C, 59.46; H,5.47; N, 16.68

EXAMPLE 14

¹H NMR (CDCl₃) o 1.07 (d, J=6.1Hz, 6 H), 1.78-1.84 (m, 3 H), 4.42 (bt,J=8.0 Hz, 2 H), 5.21 (s, 2 H), 5.77 (s, 2 H), 7.14 (d, J=6.2 Hz, 1 H),7.33-7.49 (m, 8 H), 7.94 (d, J=8.0 Hz,1 H), 8.34 (d, J=6.3 Hz, 1 H),9.00 (s, 1 H); MS m/e 376 (MH⁺).

EXAMPLE 15

¹H NMR (CD₃OD) δ 0.97 (d, J=6.3 Hz, 6 H), 1.44-1.49 (m, 2 H), 1.62-1.73(m, 1 H),2.25 (s, 3 H), 4.27-4.33 (m, 2 H), 5.21 (s, 1 H), 5.38 (s, 2H), 5.42 (s, 1 H), 7.02-7.08 (m, 2 H), 7.23 (dd, J=4.5, 9.0 Hz, 1 H),7.45 (dd, J=2.4, 9.3 Hz, 1 H), 8.33 (d, J=5.1 Hz, 1 H), 8.17 (s, 1 H);IR (KBr, cm⁻¹) 2960, 1713, 1605, 1495, 1455, 1399, 1333, 1163, 1140,848, 813; MS m/e 394 (MH⁺); Anal. Calcd for C₂₂H₂₄FN₅O: C, 67.16; H,6.15; N, 17.80 Found: C, 67.25; H, 5.96; N, 17.88.

EXAMPLE 16

¹H NMR (CDCl₃) δ 0.97 (d, J=6.9 Hz, 6 H), 1.43-1.50 (m, 2 H), 1.55 (d,J=7.2 Hz, 6 H), 1.55-1.75 (m, 1 H), 4.26-4.31 (m, 2 H), 4.70-4.80 (m, 1H), 5.37 (s, 2 H), 7.01-7.08 (m, 2 H), 7.22 (dd, J=4.8, 8.9 Hz, 1 H),7.44 (dd, J=2.7, 9.3 Hz, 1H), 8.29 (d, J=5.4 Hz, 1 H), 8.68 (s, 1 H); IR(KBr, cm¹) 2956, 1706, 1493, 1456, 1389, 1332, 1133, 1113, 847; MS m/e396 (MH⁺); Anal. Calcd for C₂₂H₂₆FN₅O•0.33H₂O: C, 65.82; H, 6.69; N,17.44 Found: C, 65.83; H, 6.30; N, 17.43.

EXAMPLE 17

A solution of Example 15 (4.0 g, 10.17 mmol) in a mixture of MeOH (10mL) and 6 N HCl (20 mL) was stirred at reflux overnight. The solutionwas cooled to room temperature and neutralized with concentrated NaOHsolution, and evaporated. The residue was taken up with CH₂Cl₂, driedover MgSO₄, and evaporated. The residue was triturated with hot EtOAcand filtered to give Example 17 (3.22 g, 90% yield) as a white solid.

¹H NMR (CDCl₃) δ 0.99 (d, J=6.6 Hz, 6 H), 1.50-1.55 (m, 2 H), 1.71-1.77(m, 1 H), 4.25-4.31 (m, 2 H), 5.36 (s, 2 H), 6.97 (d, J=5.1 Hz, 1 H),7.06 (dt, J=2.4, 9.3 Hz, 1 H), 7.23 (dd, J=4.5, 8.7 Hz, 1 H), 7.43 (dd,J=2.4, 9.3 Hz, 1 H), 8.29 (d, J=5.1 Hz, 1 H), 8.62 (s, 1 H), 9.89 (bs, 1H); IR (KBr, cm⁻¹) 2958, 1720, 1622, 1491, 1455, 1139, 1014, 958, 894,813; MS m/e 375 (MH⁺); Anal. Calcd for C₁₉H₂₀FN₅O: C, 64.58; H, 5.70; N,19.82 Found: C, 64.26; H, 5.58; N, 19.85.

EXAMPLE 18

¹H NMR (CDCl₃) δ 0.99 (d, J=6.7 Hz, 6 H), 1.54-1.59 (m, 2 H), 1.69-1.73(m, 1 H), 4.29 (t, J=9.2 H, 2 H), 5.20 (s, 2 H), 5.43 (s, 2 H), 6.86 (d,J=.4 Hz, 1 H), 7.05 (dt, J=2.4, 9.1 Hz, 1 H), 7.24 (dd, J=4.5, 8.9 Hz, 1H), 7.41 (dd, J=2.4, 9.3 Hz, 1 H), 7.49 (d, J=8.7 Hz, 2 H), 8.21 (d,J=8.7 Hz, 2 H), 8.29 (d, J=5.2 Hz, 1 H), 8.76 (s, 1 H);IR(KBr,cm⁻¹)3424, 2959, 1716, 1611, 1524, 1492, 1346, 1176, 1137, 800;MS m/e 489 (MH⁺). Anal. Calcd for C₂₆H₂₅FN₃O₃: C, 63.92; H, 5.16; N,17.20 Found: C, 63.95; H, 5.13; N, 17.22.

EXAMPLE 19

A mixture of Example 18 (1.52 g, 3.11 mmol) and 10% palladium on carbon(150 mg) in MeOH (50 mL) and concentrated hydrochloric acid (1 mL) wasaggitated under hydrogen at 55 psi for 1.5 hours. The reaction mixturewas filtered through a pad of Celite, rinsing thoroughly with MeOH. Thefiltrate was evaporated and dried under vacuum to give Example 19 as anHCl salt (1.82 g, quantitative yield).

¹H NMR (CD₃OD) δ 1.09 (d, J=6.0 Hz, 6 H), 1.84-1.90 (m, 3 H), 4.64 (t,J=7.6 Hz, 2 H), 5.40 (s, 2 H), 5.94 (s, 2 H), 7.43-7.47 (m, 3 H), 7.52(dd, J=2.3, 8.1 Hz, 1 H), 7.70 (d, J=8.3 Hz, 2 H), 7.87 (d, J=6.5 Hz, 1H), 7.93 (dd, J=4.2, 9.1 Hz, 1 H), 8.59 (d, J=6.4 Hz, 1 H), 9.01 (s, 1H); IR (KBr, cm¹) 3411, 2869, 1748, 1655, 1621, 1517, 1496, 1130, 810;MS m/e 459 (MH⁺); Anal. Calcd for C₂₆H₂₇FN₆O₃•3HCl•2.5H₂0: C, 50.95; H,5.76; N, 13.71 Found: C, 50.72; H, 5.47; N, 13.66.

EXAMPLE 20

To a mixture of Example 19 (350 mg, 0.66 mmol) and triethylamine (200mg, 1.98 mmol) in CH₂Cl₂ cooled to 0° C. was added methanesulfonylchloride (75 mg, 0.66 mmol). The reaction mixture was allowed to warm toroom temperature and then stirred for 16 hours. The reaction mixture wasdiluted with CH₂Cl₂ (100 mL) and washed with saturated aqueous sodiumbicarbonate solution (10 mL) and brine solution (10 mL). The aqueouslayer was back-extracted with CH₂Cl₂. The combined organic extracts weredried over anhydrous MgSO₄, and evaporated. Trituration of the resultingpale yellow solid with Et₂O gave the title compound (quantitativeyield).

¹H NMR (CD₃OD) δ 1.06 (d, J=6.3 Hz, 6 H), 1.75-1.81 (m, 3 H), 2.93 (s, 3H), 4.46 (t, J=8.2 Hz, 2 H), 5.28 (s, 2 H), 5.64 (s, 2 H), 7.18 (t,J=2.5, 9.2 Hz, 1 H), 7.23-7.29 (m, 3 H), 7.46 (d, J=8.6 Hz, 2 H), 7.60(dd, J=4.4, 8.9 Hz, 1 H), 7.77 (d, J=6.5 Hz, 1 H), 8.48 (d, J=6.7 Hz, 1H), 8.78 (s, 1 H); IR(KBr, cm⁻¹) 3441, 2959, 1736, 1617, 1515, 1332,1150, 1040, 821; MS m/e 537 (MH⁺); Anal. Calcd for C₂₇H₂₉FN₆O₃S•4.5H₂O:C, 52.50; H, 6.20; N, 13.61 Found: C, 52.20; H, 5.79; N, 12.79.

EXAMPLE 21

To a mixture of Example 19 (400 mg, 0.75 mmol) and triethylamine (229mg, 2.26 mmol) in CH₂Cl₂ cooled to 0° C. was added acetyl chloride (74mg, 0.94 mmol) followed by a catalytic amount of dimethylaminopyridine(10 mg). The reaction was allowed to warm to room temperature and a paleyellow precipitate came out of solution. After 1 hour, the reactionmixture was diluted with CH₂Cl₂ and washed with saturated aqueous sodiumbicarbonate solution and brine. The aqueous layer was back-extractedwith CH₂Cl₂. The combined organic extracts were dried over anhydrousMgSO₄, and evaporated. Trituration of the resulting white solid withEt₂O gave Example 21 (321 mg, 85% yield).

¹H NMR (CD₃OD) δ 0.96 (d, J=0.96 Hz, 6 H), 1.54-1.59 (m, 2 H), 1.67-1.70(m, 1 H), 2.10 (s, 3 H), 4.36 (t, J=8.2Hz, 2 H), 5.13 (s, 2 H), 5.51 (s,2 H), 7.11 (dt, J=2.5, 9.2 Hz, 1 H), 7.21 (d, J=5.4 Hz, 1 H), 7.30 (dd,J=2.4,9.3 Hz, 1 H), 7.37 (d, J=8.6 Hz, 2 H), 7.49 (dd, J=4.5, 9.0 Hz, 1H), 7.54 (d, J=8.6 Hz, 2 H), 8.19 (d,J=5.4 Hz, 1 H), 8.35 (s, 1 H); IR(KBr, cm⁻¹) 3424, 2960, 1724, 1691, 1610, 1517, 1507, 1455, 1402, 1319,1136, 810; MS m/e 501 (MH⁺); Anal. Calcd for C₂₈H₂₉FN₆O₂•0.5H₂O: C,66.00; H, 5.93; N, 16.49 Found: C, 65.79; H, 6.12; N, 16.29.

EXAMPLE 22

To a solution of the Example 20 (50 mg, 0.10 mmol) in DMF (5 mL) wasadded m-chloroperbenzoic acid (34 mg, 0.20 mmol). The mixture wasstirred at room temperature for 16 hours. The solvent was evaporatedunder reduced pressure. The resulting residue was triturated with waterand filtered. The aqueous filtrate was extracted with EtOAc and thecombined extracts were dried over MgSO₄, and evaporated. The residuecombined with the solid obtained from trituration were subjected toflash chromatography (gradient, CH₂Cl₂/5% ammonium hydroxide in MeOH,40:1 to 20:1) to give Example 22 as a white solid (21 mg, 41% yield).

¹H NMR (DMSO-d₆) δ 0.95 (d, J=6.5 Hz, 6 H), 1.57-1.60 (m, 2 H),1.66-1.74 (m, 1 H), 2.02 (s, 3 H), 4.32 (t, J=7.7 Hz, 2 H), 5.05 (s, 2H), 5.41 (s, 2 H), 7.13 (t, J=8.7 Hz, 1 H), 7.24 (d, J=6.7 Hz, 1 H),7.29 (d, J=8.2 Hz, 1 H), 7.41 (d, J =8.6 Hz, 1 H), 7.54 (d, J=8.2 Hz, 1H), 7.55-7.59 (m, 1 H), 7.96 (d, J=6.3 Hz, 1 H), 8.37 (s, 1 H); IR (KBr,cm⁻¹) 3428, 2956, 1720, 1678, 1600, 1551, 1514, 1465, 1407, 1320, 1162,1146, 802; MS m/e 517 (MH⁺); Anal. Calcd for C₂₈H₂₉FN₆O₃•0.5H₂O: C,63.99; H, 5.75; N, 15.99 Found: C, 64.08; H, 5.57; N, 15.82.

EXAMPLE 23

¹H NMR (CD₃OD) δ 0.98 (d, J=6.6 Hz, 6 H), 1.59-1.64 (m, 2 H), 1.69-1.73(mi, 1 H), 3.09 (s, 3 H), 4.39 (t, J=8.1 Hz, 2 H), 5.31 (s, 2 H), 5.52(s, 2 H), 7.12 (dt, J=2.5, 9.2 Hz, 1 H), 7.23 (d, J=5.4 Hz, 1 H), 7.29(dd, J=2.4, 9.2 Hz, 1 H), 7.51 (dd, J=4.5, 8.9 hz, 1 H), 7.66 (d, J=8.4Hz, 2 H), 7.94 (d, J=8.4 Hz, 2 H), 8.22 (d, J=1.7 Hz, 1 H), 8.39 (s, 1H); IR (KBr, cm⁻¹) 3423, 2959, 1715, 1613, 1602, 1497, 1454, 1407, 1307,1148, 1090, 808, 520; MS m/e 522 (MH⁺).

EXAMPLE 24

¹H NMR (CD₃OD) δ 1.85-1.90 (m, 2 H), 1.90 (s, 3 H), 2.27 (t, J=7.5 Hz, 2H), 4.29-4.34 (t, J=7.5 Hz, 2 H), 5.03 (s, 1 H), 5.65 (s, 1 H), 6.86 (d,J=5.5 Hz, 1 H), 7.12-7.22 (m, 3 H), 7.60-7.63 (m, 1 H), 8.16 (d, J5.5Hz, 1 H), 8.65(s,1 H); IR (KBr, cm⁻¹) 3396, 2244, 1710, 1660, 1604,1493, 1458, 1399, 1332, 1166, 1140, 824, 742; MS m/e 373 (MH⁺); Anal.Calcd for C₂₂H₂₅N₅O•0.25 H₂O: C, 66.92; H, 5.48; N, 22.30 Found: C,66.58; H, 5.56; N, 22.34.

EXAMPLE 25

¹H NMR (CDCl₃) δ 1.56 (d, J=6.9 Hz, 6 H), 1.98-2.08 (m, 2 H), 2.45 (t,J=7.2 Hz, 2 H), 4.49 (t, J=7.2 Hz, 2 H), 4.70-4.74 (m, 1 H), 5.40 (s, 2H), 7.06 (d, 3J 5.2 Hz, 1 H), 7.33-7.39 (m, 3 H), 7.78-7.81 (m, 1 H),8.31 (d, J=5.2 Hz, 1 H), 8.81 (s, 1 H); IR (KBr, cm⁻¹) 3412, 2981, 2246,1700, 1608, 1496, 1459, 1391, 1117, 748; MS m/e 375 (MH⁺).

EXAMPLE 26

¹H NMR (CDCl₃) δ 1.03-1.06 (m, 2 H), 1.97-1.24 (m, 2 H), 2.13-2.18 (m, 2H), 2.47 (t, J4.2 Hz, 2 H), 2.96-3.00 (m, 1 H), 4.51 (t, J4.4 Hz, 2 H),4.16 (s, 2 H), 7.27-7.35 (m, 4 H), 7.38 (dd, J=0.8,4.2 Hz, 1 H), 7.77(dd, J=0.9, 4.4 Hz, 1 H), 8.37 (d, J=3.4 Hz, 1 H), 8.56 (s, 1 H); IR(KBr, cm¹) 3405, 2245, 1702, 1608, 1500, 1408, 1172, 1024, 820, 743; MSm/e 373 (MH⁺); Anal. Calcd for C₂₁H₂₀N₈O•0.875H₂O: C, 64.98; H, 5.64; N,21.65 Found: C, 65.06; H, 5.36; N, 21.51.

EXAMPLE 27

¹H NMR(CD₃OD) δ 0.53-0.54 (m, 2 H), 0.64-0.66 (m, 2 H), 1.31-1.37 (m, 1H), 2.30-2.34 (m, 2 H), 2.68 (t, J=7.2 Hz, 2 H), 4.02 (d, J=7.2 Hz, 2H), 4.63 (t, J=7.4 Hz, 2 H), 5.72 (s, 2 H), 7.39 (t, J=7.0 Hz, 1 H),7.43 (t, J=7.1 Hz, 1 H), 7.63 (d, J=7.9 Hz, 1 H), 7.73 (d, J=8.1 Hz, 2H), 7.92 (d, J=6.5 Hz, 1 H), 8.55 (d, J =6.5 Hz, 1 H), 8.81 (s, 1 H); IR(KBr, cm) 3448, 2250, 1748, 1676, 1522, 1201, 1131, 720; MS m/e 387(MH⁺).

EXAMPLE 28

¹H NMR (CDCl₃) δ 1.81 (s, 9 H), 2.05-2.06 (m, 2 H), 2.46 (t, J=7.2 Hz, 2H), 4.48 (t, J=7.6 Hz, 2 H), 5.38 (s, 2 H), 7.31-7.36 (m, 4 H), 7.78 (m,1 H), 8.24 (d, J=5.8 Hz, 1 H), 8.84 (s, 1 H); IR (KBr, cm¹) 3406, 2937,2246, 1706, 1493, 1458, 1387, 1157, 1138, 746; MS m/e 389 (MH⁺).

EXAMPLE 29

¹H NMR (DMSO-d₆) δ 2.09-2.12(m, 2 H), 2.63 (t, J=7.4 Hz, 2 H), 4.43 (t,J=7.5 Hz, 2 H), 5.28 (s, 2 H), 5.52 (s, 2 H), 7.21 (t, J=7.2 Hz, 1 H),7.26 (t, J=7.2 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 7.60-7.63 (m, 4 H),7.92 (d, J=8.4 Hz, 2 H), 8.23 (d, J=5.3 Hz, 1 H), 8.50 (s, 1 H); IR(KBr, cm⁻¹) 3426, 2246, 1716, 1407, 1150, 760; MS m/e 501 (MH⁺); Anal.Calcd for C₂₇H₂₈FN₅O₃S: C, 62.17; H, 5.17; N, 13.43 Found: C, 62.03; H,5.45; N, 13.34.

EXAMPLE 30

¹H NMR (CDCl₃) δ 1.54 (d, J=7.0 Hz, 6 H), 1.99-2.05 (m,2 H), 2.45 (t,J=7.2 Hz, 2 H), 4.47 (t, J=7.6Hz, 2 H), 4.70 (m, 1H), 5.36 (s, 2 H),7.06-7.10 (m, 2 H), 7.27-7.30 (m, 1 H), 7.45 (q, J=2.4, 9.1 Hz, 1 H),8.31 (d, J=4.0 Hz, 1 H), 8.78 (s, 1 H); R (KBr, cm⁻¹) 3432, 2953, 2360,2245, 1718, 1698, 1284, 1139; MS m/e 393 (MH⁺); Anal. Calcd forC₂₁H₂₁FN₆O: C, 64.27; H, 5.39; N, 21.41 Found: C, 64.23, H, 5.44; N,21.24.

EXAMPLE 31

¹H NMR (CDCl₃) δ 1.53 (d, J=7.0 Hz, 6 H), 1.96-2.03 (m, 2 H), 2.45 (t,J=7.2 Hz, 2 H), 4.41 (t, J=7.6 Hz, 2 H), 4.70 (m, 1 H), 5.34 (s, 2 H),6.99-7.06 (m, 3 H), 7.67-7.70 (m, 1 H), 8.29 (d, J=4.0 Hz, 1H), 8.76 (s,1 H); IR (KBr, cm¹) 3423, 2941, 2247, 1710, 1492, 1390, 808; MS m/e 393(MH⁺).

EXAMPLE 32

¹H NMR (CDCl₃) δ 1.03-1.06 (m, 2 1.17-1.22 (m, 2H), 2.25-2.31 (m, 2 H),2.93 (s, 3 H), 2.98-3.01 (m, 1 H), 3.10 (t, J=7.4 Hz, 2 H), 4.54 (t,J=7.5 Hz, 2 H), 5.42 (s, 2 H), 7.25-7.39 (m, 4 H), 7.76 (d, J=7.1 Hz, 1H), 8.36 (d, J=5.3Hz, I H), 8.79 (s, 1 H); IR (KBr, cm⁻¹) 3423, 2927,1718, 1608, 1499, 1459, 1409, 1311, 1289, 1128, 748; MS m/e 426(MH⁺);Anal. Calcd for C₂₁H₂₃N₅O₃S: C, 59.27; H, 5.44; N, 16.45 Found: C,59.03; H, 5.52; N, 16.31.

EXAMPLE 33

¹H NMR (DMSO-d₆) δ 2.13-2.20 (m, 2 H), 3.01 (s, 3 H), 3.26 (t, J=7.8 Hz,2 H), 4.50 (t, J=7.5 Hz, 2 H), 4.91 (q, J=9.3 Hz, 2 H), 5.53 (s, 2 H),7.20 (t, J=7.3 Hz, 1 H), 7.28 (t, J=7.7 Hz, 1 H), 7.45 (d, J=5.3 Hz, 1H), 7.64 (d, J=8.1 Hz, 1 H) 8.32 (d, J=5.3 Hz, 1 H), 8.52 (s, 1 H); IR(KBr, cm⁻¹) 3441, 1725, 1498, 1460, 1408, 1294, 1265, 1167, 1125, 746;MS m/e 468 (MH⁺); Anal. Calcd for C₂₀H₂₀F₃N₅O₃S•0.375 H₂O: C, 50.66; H,4.41; N, 14.76 Found: C, 50.83; H, 4.34; N, 14.41.

EXAMPLE 34

¹H NMR (CD₃OD) δ 1.47 (d, J=6.9 Hz, 6 H), 2.14-2.17 (m, 2 H), 3.00 (s, 3H), 3.24 (t, J=7.8 Hz, 2 H), 4.50 (d, J=7.5 Hz, 2 H), 4.63-4.66 (m, 1H), 5.44 (s, 2 H), 7.16 (dt, J=2.5, 9.2 Hz, 1 H), 7.41-7.45 (m, 2 H),7.67 (dd, J=4.8, 8.9 Hz, 1 H), 8.23 (d, J=5.4 Hz, 1 H), 8.47 (s, 1 H);IR (KBr, cm⁻¹)3423, 2984, 2937, 1702, 1608, 1495, 1457, 1391, 1293,1135, 1116, 963, 809; MS m/e 446 (MH⁺); Anal. Calcd for C₂₁H₂₄FN₅O₃S: C,56.61; H, 5.43; N1, 15.71 Found: C, 56.46; H, 5.55; N, 15.62.

EXAMPLE 35

¹H NMR (CD₃OD) δ 0.91-0.93 (m, 2 H), 1.06-1.07 (m, 2 H), 2.99-3.01 (m, 1H), 3.00 (s, 3 H), 3.23 (t, J=7.7 Hz, 2 H), 4.49 (t, J=7.5 Hz, 2 H),5.41 (s, J=2 H), 7.15 (dt, J=, 1 H), 7.29 (dd, J=2.0, 5.3 Hz, 1 H), 7.43(dd, J=2.5, 9.8 Hz, 1 H), 7.67 (dd, J=4.7, 8.9 Hz, 1 H), 8.26 (d, J=5.3Hz, 1 H), 8.44 (s, 1 H); IR (KBr, cm⁻¹) 3423, 3014, 1708, 1609, 1498,1455, 1415, 1315, 1294, 1171, 1131, 957, 819; MS m/e 444 (MH⁺); Anal.Calcd for C₂₁H₂₂FN₅O₃S: C, 56.87; H, 5.00; N, 15.79 Found: C, 56.76; H,5.15; N, 15.69.

Example 35 was converted to an oxalate salt by adding 1 equivalent ofoxalic acid to a MeOH solution of 35 and evaporating the solvent.

¹H NMR (CD₃OD) δ 2.26 (s, 3 H), 2.26-2.36 (m, 2 H), 2.64 (t, J=7.5 Hz, 2H), 4.62 (t, J=7.5 Hz, 2 H), 5.29 (s, 1 H), 5.45 (s, 1 H), 5.58 (s, 2H), 7.16 (dd, J=5.4, 8.1 Hz, 1 H), 7.34-7.44 (m, 2 H), 7.54-7.71 (m, 2H), 7.70 (dl, J=8.1 Hz, 1 H), 8.01 (dd, J=0.9, 5.4 Hz, 1 H); IR (KBr,cm⁻¹) 3405, 2954, 2244, 1702, 1611, 1476, 1456, 1400, 1276, 1188, 1158,795, 749; MS m/e 373 (MH⁺); Anal. Calcd for C₂₁H₂₀N₆O•C₂H₂O₄•0.25H₂O: C,59.16; H, 4.86; N, 18.00 Found: C, 58.90; H, 4.83; N, 18.24.

EXAMPLE 36

¹H NMR (CDCl₃) 62.19-2.45 (m, 2 H), 2.45 (s, 3 H), 2.48 (t, J=7.1 Hz, 2H), 4.61 (t, J=7.4 Hz, 2 H), 5.19 (s, 1 H), 5.34 (s, 1H), 5.48 (s, 2 H),7.03 (dd, J=5.2, 7.9 Hz, 1 H), 7.26-7.33 (m, 3 H), 7.80 (d, J=8.0 Hz, 1H), 8.10 (dd,J=1.4, 5.2 Hz, 1 H).

EXAMPLE 37

¹H NMR (CDCl₃) δ 2.28-2.34 (s over m, 5 H), 2.94 (s, 3 H), 3.16 (t,J=7.2 Hz, 2 H), 4.59 (t, J=7.9 Hz, 2 H), 5.37 (s, 1 H), 5.47 (s, 1 H),5.54 (s, 2 H), 7.08 (dd, J =5.3, 7.8 Hz, 1 H), 7.39-7.43 (m, 2 H), 7.51(d, J=7.7 Hz, 1 H), 7.85 (d, J=7,3 Hz, 1 H), 8.05 (bs, 1 H), 8.09 (dd,J=1.0, 5.2 Hz, 1 H); IR (KBr, cm⁻¹) 3423, 1708, 1618, 1453, 1402, 1295,1131, 750; MS m/e 426(M); Anal. Calcd for C₂₁H₂₃N₅O₃S: C, 59.28; H,5.44; (t, 16.45 Found: C, 59.11; H, 5.36; N, 16.35.

EXAMPLE 38

¹H NMR (CDCl₃) δ 1.06-1.11 (m, 4 H), 2.49-2.54 (m, 2 H), 2.94-2.99 (m, 1H), 3.24 (t, J=6.7 Hz, 2 H), 4.75 (t, J=7.1 Hz, 2 H), 5.70 (s, 2 H),7.05 (dd, J=5.3, 7.7 Hz, 1 H), 7.37-7.44 (m, 3 H), 7.54 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1 H), 7.98 (d, J=4.8 Hz, 1 H); IR (KBr, cm⁻¹)3435, 1716, 1617, 1486, 1460, 1425, 1295, 1131, 747; MS m/e 426 (MH⁺).

EXAMPLE 39

¹H NMR (DMSO-d₆) δ 1.02-1.07 (m, 4 H), 2.08-2.14 (m, 2 H), 21.64 (,J=7,4Hz, 2 H), 3.02-3.03 (m, 1 H), 4.42 (t, J=7.4 Hz, 2 H), 5.44 (s, 1 H),7.19 (t, J=7.5 Hz, 1 H), 7.28 (t, J=7.2 Hz, 1 H), 7.56 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1 H), 8.46 (s, 1 H), 8.66 (s, 1 H); IR (KBr,cm⁻¹) 3452, 2244, 1731, 1718, 1612, 1488, 1422, 1407, 1317, 746; MS m/e374 (MH⁺); Anal. Calcd for C₂₀H₁₉N₇O: C, 64.33; H, 5.12; N, 26.25;Found: C, 64.00; H, 5.20; N, 26.12.

EXAMPLE 40

¹H NMR (CDCl₃) δ 2.07-2.13 (m, 2 H), 2.48 (t, J=6.9 Hz, 2 H), 4.52 (d,J=7.6 Hz, 2 H), 4.59-4.64 (m, 2 H), 5.47 (s, 2 H), 7.33-7.44 (m, 3 H),7.80 (d, J=7.5 Hz, 1 H), 8.76 (s, 1 H), 8.88 (s, 1 H); MS m/e 416 (MH⁺);Anal. Calcd for C₁₉H₁₆ F₃N₇O: C, 54.94; H, 3.88; N, 23.60 Found: C,54.87; H, 3.78; N, 23.66.

EXAMPLE 41

¹H NMR (CDCl₃) δ 2.12-2.15 (,2 H), 2.43 (t, J=7.0 Hz, 2 H), 3.02 (s, 3H), 4.51 (,J=7.4 Hz, 2 H), 5.22 (s, 2 H), 5.45 (s, 2 H), 7.32-7.42 (m, 3H), 7.69 (d, J 8.4 Hz, 2 H), 7.77-7.79 (m, 1 H), 7.91-7.93 (m, 2 H),8.73 (s, 1 H), 8.83 (s, 1 H); MS m/e 502 (MH⁺).

EXAMPLE 42

¹H NMR (CDCl₃) δ 2.12-2.15 (m, 2 H), 2.44 (t, J=7.0 Hz, 2 H), 3.02 (s, 3H), 4.49 (t, J=7.4 Hz, 2 H), 5.23 (s, 2 H), 5.41 (s, 2 H), 7.10-7.14 (m,1 H), 7.32-7.34 (m, 1 H), 7.43 (dd, J=2.4, 9.0 Hz, 1 H), 7.69 (d, J=8.3Hz, 2H), 7.92 (d, J =8.3 Hz, 2 H), 8.74 (s, 1 H), 8.80 (s, 1 H); IR(KBr, cm) 3441, 2928, 2244, 1718, 1609, 1492, 1406, 1300, 1150; MS m/e520 (MH⁺); Anal. Calcd. for C₂₅H₂₂FN₃O₃S: C, 57.79; H, 4.26; N, 18.87Found: C, 57.49; H, 4.11; N, 18.55.

EXAMPLE 43

¹H NMR (CDCl₃) δ 1.17-1.18 (m, 2 H), 2.31-2.37 (m, 2 H), 2.97 (s, 3 H),3.01-3.06 (m, 1 H), 3.15 (t, J=7.2 Hz, 2 H), 4.58 (t, J=7.5 Hz, 2 H),5.41 (s, 1 H), 7.30-7.36 (m, 2 H), 7.42 (d, J=7.4 Hz, 1 H), 7.76-7.78(dd,J=1.2, 7.2 Hz, 1 H), 8.73(s, 1 H), 8.74 (s, 1 H); IR (KBr, cm⁻¹)3424, 1721, 1615, 1493, 1407, 1313, 1126, 750; MS m/e 427 (MH⁺); Anal.Calcd for C₂₀H₂₂N₆OS•H₂O: C, 54.04; H, 5.44; N, 18.91 Found: C, 53.95;H, 5.54; N. 18.75.

EXAMPLE 44

¹H NMR (CDCl₃) δ 1.84 (s, 9 H), 2.30-2.35 (m, 2 H), 3.13 (t, J=7.2 Hz,2H), 4.58 (t, J=7.6 Hz, 2 H), 5.38 (s, 1 H), 7.30-7.35 (m, 2 H), 7.42(d, J=7.4 Hz, 1 H), 7.76-7.78 (dd, J=1.2,7.2 Hz, 1 H), 8.66 (s, 1 H),8.73 (s, 1 H); IR (KBr, cm⁻¹): 3431, 2927, 1718, 1616, 1469, 1444, 1469,1444, 1296, 1134, 747; MS m/e 443 (MH⁺); Anal. Calcd forC₂₁H₂₆N₆O₃S•H₂O: C, 55.86; H, 6.03; N, 18.61 Found: C, 55.87; H, 5.88;N, 18.44.

EXAMPLE 45

¹H NMR (CDCl₃) δ 2.25-2.29 (m, 2 H), 2.97 (s, 3 H), 3.14 (t, J=7.0 Hz, 2H), 1 5 4.56-4.64 (m, 4 H), 5.49 (s, 2 H), 7.32-7.39 (m, 2 H), 7.44 (d,J=7.4 Hz, 1 H), 7.78-7.80 (dd, J=1.4, 7.2 Hz, 1 H), 8.76 (s, 1 H), 8.85(s, 1 H); MS m/e 469 (MH⁺).

EXAMPLE 46

¹H NMR (CDCl₃) δ 0.71-0.74 (m, 2 H), 1.03-1.07 (m, 2 H), 2.63-2.66 (m, 1H), 3.66 (s, 3 H), 5.39 (s, 2 H), 5.47 (s, 2 H), 6.50 (m, 4 H), 6.99 (d,J=5.3 Hz, 1 H), 7.20 (d, J=8.0 Hz, 1 H), 7.26 (m, 1 H), 7.31 (m, 1 H),7.85 (d,J J8.0 Hz, 1 H), 8.27 (d, J=5.0 Hz, 1 H), 8.53 (s, 1 H); MS m/e426 (MH⁺).

EXAMPLE 47

A stirred suspension of Example 46 (11.75 g, 27.6 mmol) in CH₃CN (150mL) was treated with ceric ammonium nitrate (CAN, 60.60 g, 110 mmol) anddiluted with water (25 mL) to give a homogeneous solution which wasstirred at room temperature for 24 hours. The mixture was concentratedin vacuo to a volume of 50 mL, then diluted with H₂O (100 mL) and againconcentrated until 100 mL remained and a yellow solid had precipitatedfrom solution. The yellow solid was isolated from the chilled suspensionby filtration and was identified as the 4-methoxybenzaldehydeby-product. The filtrate was then diluted with H₂O to 400 mL and MeOH(600 mL) was added. To the resulting solution was added a saturatedaqueous solution of sodium potassium tartrate until the pH of thesolution reached 6 and a very finely divided powder precipitated. Thereaction mixture was centrifuged and the liquid was decanted away fromthe solid and concentrated in vacuo. The residue was redissolved inwater (250 mL) and the resulting solution was extracted with CH₂Cl₂(8×100 mL). The organic extracts were combined and concentrated in vacuoto a brown glassy solid which was redissolved in minimum CH₂Cl₂. After afew minutes, a beige powder precipitated from solution. Et₂O was addedto the mixture and the solid was isolated by filtration, rinsed withEt₂O, and dried under high vacuum to give 6.62 g (79% yield) of Example47 as a beige powder.

¹H NMR (DMSO-d₆) δ 0.92-0.97 (m, 2 H), 1.06-1.10 (m, 2 H), 2.97-3.01 (m,1 H), 5.30 (s, 2 H), 7.14-7.17 (m, 2 H), 7.30 (d, J5.4Hz, 1 H), 7.50 bs,2 H), 8.25-8.28 (m, 2 H), 12.54 (bs, 1 H); MS m/e 306 (MH⁺).

EXAMPLE 48

¹H NMR (CDCl₃) δ 0.97-1.00 (m, 2 H), 1. 12-1.16 (m, 2 H), 2.09-2.15 (m,2 H), 2.99-3.03 (m, 1 H), 3.82 (t, J=6.8 Hz, 2 H), 4.42 (t, J=7.9 Hz, 2H), 5.36 (s, 2 H), 7.21-7.28 (m, 3 H), 7.32 (d, J=7.7 Hz, 1 H),7.69-7.74 (m, 3 H), 7.81-7.85 (m, 2 H), 8.35 (d, J=5.0 Hz, 1 H), 8.79(s, 1 H); MS m/e 493 (MH⁺).

EXAMPLE 49

Example 48 (2.58 g, 5.24 mmol) was treated with hydrazirie hydrate (2.62g, 52.4 mmol) in MeOH (100 mL) and the mixture was heated to reflux for5 hours. The resulting mixture was passed through a 50 mL bed of AG50W-X2 strong cation exchange resin (Bio-Rad Laboratories), and the bedwas rinsed with MeOH (300 mL). The yellow eluent was discarded, and theproduct was eluted from the resin with 2M ammonia in MeOH (500 mL). Theammonia eluent was concentrated in vacuo to give 1.85 g (97% yield) ofExample 49 as an off-white powder.

¹H NMR (DMSO-d₆) δ 0.92 (s, 2 H), 1.07 (d, J=5.8, 2 H), 1.74 (t, J=6.8Hz, 2 H), 2,57 (t, J=6.2 Hz, 2 H), 2.99-3.01 (m, 1 H), 4.39 (t, J=7.1Hz, 2 H), 5.43 (s, 2 H), 7.17 (t, J=7.4Hz, 1 H), 7.24 (t, J=7.5 Hz, 1H), 7.29 (d, J=5.1 Hz, 1 H), 7.58 (t, J=8.6 Hz, 2 H), 8.25 (d, J=5.2 Hz,1 H), 8.39 (s, 1 H); MS m/e 363 (MU+).

EXAMPLE 50

A mixture of Example 49 (0.0 50 g, 0. 14 mmol) and polystyrenediisopropylethylamine resin (PS-DIEA resin, Argonaut, 0.075 g, 0.28mmol) in anhydrous CH₂Cl₂ (1 mL) was treated with acetic anhydride(0.141 g, 1.38 mmol) and stirred at room temperature for 18 hours.Solids which precipitated from solution were redissolved by the additionof chloroform (1 mL), and the reaction mixture was filtered to removethe resin. The filtrate was concentrated in vacuo, and the residue waspurified by preparative HPLC (gradient, 10% MeOH in H₂O with 0.1% TFA to90% MeOH in H₂O with 0.1% TFA) to give 0.074 g (>100% yield) of thetrifluoroacetic acid salt of Example 50 as a glassy, colorless solid.

¹H NMR (DMSO-d₆) δ 0.99-1.02 (m, 2 H), 1.13-1.17 (m, 2 H), 1.84 (s, 3H), 1.95 (t, J=7.3 Hz, 2 H), 3.14-3.17 (m, 3 H), 4.41 (t, J=7.5 Hz, 2H), 5.57 (s, 2 H), 7.25 (t, J=7.4 Hz, 1 H), 7.33 (t, J=7.4 Hz, 1 H),7.58 (d, J=8.0 Hz, 1 H), 7.68 (d, J=8.1 Hz, 1 H), 7.83 (d, J=6.4 Hz, 1H), 7.99 (t, J=5.2 Hz, 1 H), 8.62 (d, J =6.2 Hz, 1 H), 8.83 (s, 1 H); MSm/e 405 (MH⁺).

EXAMPLE 51

Example 51 was prepared according to the same procedure described forExample 50 using trifluoroacetic anhydride.

¹H NMR (DMSO-d₆) δ 0.98-1.01 (m, 2 H), 1.13-1.17 (m, 2 H), 2.03-2.08 (m,2 H), 3.14-3.18 (m, 1 H), 3.33-3.37 (m, 2 H), 4.42 (t, J=7.5 Hz, 2 H),5.54 (s, 2 H), 7.20-7.23 (m, 1 H), 7.29-7.23 (m, 1 H), 7.56 (d, J=8.0Hz, 1 H), 7.65 (d, J=8.1 Hz, 1 H), 7.81 (d, J=6.3 Hz, 1 H), 8.61 (d,J=6.3 Hz, 1 H), 8.81 (s, 1 H), 9.54-9.56 (m, 1 H); MS m/e 459 (MH⁺).

EXAMPLE 52

Example 52 was prepared according to the same procedure described forExample 50 using methanesulfonyl chloride.

¹H NMR (DMSO-d₆) 5 1.04-1.07 (m, 2 H), 1.14-1.17 (m, 2 H), 2.12 (t,J=7.4 Hz, 2 1H), 2.96 (s, 3 H), 3.16-3.18 (m, 3 H), 4.58 (t, J=7.6 Hz, 2H), 5.82 (s, 2 H), 7.23-7.25 (m, 1 H), 7.47 (t, J=7.6 Hz, 1 H), 7.54 (t,J=7.7 Hz, 1 H), 7.75 (d, J=8.1 Hz, 1 H), 7.88 (d, J=6.5 Hz, 1 H), 7.94(d, J=8.3 Hz, 1 H), 8.66 (d, J=6.5 Hz, 1 H), 8.90 (s, 1 H); MS m/e 441(MH⁺).

EXAMPLE 53

Example 53 was prepared according to the same procedure described forExample 50 using cyclopropanecarbonyl chloride.

¹H NMR (DMSO-d₆) δ 0.63-0.69 (m, 4 H), 0.98-1.02 (m, 2 H), 1.13-1.17 (m,2 H), 1.53-1.58 (m, 1 H), 1.94-2.00 (m, 2 H), 3.14-3.20 (m, 3 H), 4.40(t, J=7.4 Hz, 2 H), 5.55 (s, 2 H), 7.23 (t, J=7.5 Hz, 1 H), 7.31 (t,J=7.5 Hz, 1 H), 7.56 (d, J=8.0 Hz, 1 H), 7.65 (d, J=8.1 Hz, 1 H), 7.82(d, J=6.3 Hz, 1 1H), 8.21 (t, J=5.1 Hz, 1 H), 8.61 (d, J=6.2 Hz, 1 H),8.82 (s, 1 H); MS m/e 431 (MH⁺).

EXAMPLE 54

Example 54 was prepared according to the same procedure described forExample 50 using isoxazole-5-carbonyl chloride.

¹H NMR (DMSO-d₆) δ 0.97-1.00 (m, 2 H), 1.12-1.16 (m, 2 H), 2.06-2.12 (m,2 H), 3.13-3.17 (m, 1 H), 3.39-3.43 (m, 2 H), 4.46 (t, J=7.5 Hz, 2 H),5.56 (s, 2 H), 7.06 (s, 1 H), 7.22 (t, J=7.4 Hz, 1 H), 7.30 (t, J=7.4Hz, 1 H), 7.56 (d, J=8.1 Hz, 1 H), 7.67 (d, J=8.1 Hz, 1 H), 7.81 (d,J=6.3 Hz, 1 H), 8.60 (d, J=6.2 Hz, 1 H), 8.75 (s, 1 H), 8.81 (s, 1 H),9.08 (t, J=5.5 Hz, 1 H); MS m/e 458 (MH⁺).

EXAMPLE 55

Example 55 was prepared according to the same procedure described forExample 50 using methyl chloroformate.

¹H NMR (DMSO-d₆) δ 0.90-0.93 (m, 2 H), 1.03-1.09 (m, 2 H), 1.80-1.86 (m,2 H), 2.98-3.02 (m, 1 H), 3.05-3.08 (m, 2 H), 3.53 (s, 3 H), 4.35 (t,J=7.5 Hz, 2 H), 5.38 (s, 2 H), 7.17 (t, J=7.7 Hz, 1 H), 7.23-7.29 (m, 3H), 7.57 (d, J8.2 Hz, 2 H), 8.25 (d, J=5.0 Hz, 1 H), 8.40 (s, 1 H); MSmi/e 421 (MH⁺).

EXAMPLE 56

Example 56 was prepared according to the same procedure described forExample 50 using ethyl chloroformate.

¹H NMR (DMSO-d₆) δ 0.89-0.94 (m, 2 H), 1.03-1.09 (m, 2 H), 1.16 (t,J=7.1 Hz, 3 H), 1.80-1.86 (m, 2 H), 2.98-3.03 (m, 1 H), 3.04-3.08 (m, 2H), 4.00 (q, J 7.1 Hz, 2 H), 4.35 (t, J=7.5 Hz, 2 H), 5.39 (s, 2 H),7.23-7.29 (m,, 3 H), 7.29 (d, J =5.2 Hz, 1 H), 7.57 (d, J8.8 Hz, 2 H),8.25 (d, J=5.1 Hz, 1 H), 8.40 (s, 1 H); MS m/e 435 (MH⁺).

EXAMPLE 57

A solution of Example 49 (0.050 g, 0.14 mmol) in chloroform (2 mL) wastreated with ethyl isocyanatoacetate (0.018 g, 0.14 mmol) and stirredfor 15 minutes at room temperature. The mixture was concentrated invacuo. The residue was purified by preparative HPLC (gradient, 10% MeOHin H₂O with 0.1% TFA to 90% MeOH in H₂O with 0.1% TFA) to give 0.08C0 g(96% yield) of the trifluoroacetic acid salt of Example 57 as a glassy,colorless solid.

¹H NMR (DMSO-d₆) δ 0.98-1.02 (m, 2 H), 1.13-1.17 (m, 5 H), 1.91-1.97 (m,2 H), 3.10-3.12 (m, 2 H), 3.15-3.18 (m, 1 H), 3.76 (s, 2 H), 4.04 (q,J=7.1 Hz, 2 H), 4.39 (t, J=7.5 Hz, 2 H), 5.55 (s, 2 H), 6.31 (bs, 1 H),6.43 (bs, 1 H), 7.23 (t, J =7.6 Hz, 1 H), 7.29-7.33 (m, 1 H), 7.56 (d,J=8.0 Hz, 1 H), 7.66 (d, J=8.1 Hz, 1 H), 7.83 (d, J=6.3 Hz, 1 H), 8.62(d, J=5.8 Hz, 1 H), 8.83 (s, 1 H); MS m/e 492 (MH⁺).

EXAMPLE 58

Example 57 (0.061 g, 0.14 mmol) was dissolved in glacial acetic acid (2mL) and the resulting solution was heated to 120° C. in a sealed tubefor several hours. The mixture was concentrated in vacuo and the residuewas purified by preparative HPLC (gradient, 10% MeOH in H₂O with 0. 1%TFA to 90% MeOH in H₂O with 0.1% TFA) to give 0.036 g (47% yield) of thetrifluoroacetic acid salt of Example 58 as a glassy, colorless solid.

¹H NMR (DMSO-d₆) δ 0.98-1.01 (m, 2 H), 1.13-1.17 (m, 2 H), 2.01-2.07 (m,1 H), 3.13-3.18 (m, 2 H), 3.52 (t, J=6.8Hz, 2 H), 3.92 (s, 2 H),4.38-4.43 (m, 2 H), 5.55 (s, 2 H), 7.24 (t, J=7.6 Hz, 1 H), 7.29-7.33(m, 1 H), 7.56-7.59 (m, 1 H), 7.67 (d, J=8.0 Hz, 1 H), 7.81-7.83 (m, 1H), 8.09 (s, 1 H), 8.60-8.62 (m, 1 H), 8.80-8.82 (m, 1 H); MS m/e 446(MH⁺).

EXAMPLE 59

Example 49 (0.050 g, 0.14 mmol) was combined with citraconic anhydride(0.017 g, 0.15 mmol) and glacial acetic acid (2 mL). The resultingmixture was heated to 80° C. for 18 hours and then concentrated invacuo. Purification by preparative HPLC (gradient, 10% MeOH in H₂O with0.1% TFA to 90% MeOH in H₂O with 0.1% TFA) gave 0.052g (66% yield) ofthe trifluoroacetic acid salt of Example 59 as a glassy, colorlesssolid.

¹H NMR (DMSO-d₆) δ 0.97-1.00 (m, 2 H), 1.12-1.16 (m, 2 H), 2.00 (s, 3H), 2.00-2.06 (m, 2 H), 3.12-3.17 (m, 1 H), 3.56 (t, J=6.8 Hz, 2 H),4.40 (t, J=7.7 Hz, 2 H), 5.51 (s, 2 H), 6.62-6.63 (m, 1 H), 7.22 (t,J=7.4 Hz, 1 H), 7.29 (t, J=7.3 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 7.65(d, J=8.1 Hz, 1 H), 7.80 (d, J=6.2 Hz, 1 H), 8.59 (d, J=4.7 Hz, 1 H),8.80 (s, 1 H); MS m/e 457 (MH⁺).

EXAMPLE 60

Example 49 (0.050g, 0.14 mmol) was combined with4,5-dimethyl-1,3-dioxo-2-one (0.016 g, 0.14 mmol), sodium bicarbonate(0.024 g, 0.14 mmol) and anhydrous DMF (2 mL), and the resulting mixturewas stirred at room temperature for 18 hours. The mixture wasconcentrated in vacuo and the residue was purified by preparative HPLC(gradient, 10% MeOH in H₂O with 0.1% TFA to 90% MeOH in H₂O with 0.1%TFA) to give 0.029 g (37% yield) of the trifluoroacetic acid salt ofExample 60 as a glassy, colorless solid.

¹H NMR (DMSO-d₆) δ 0.98-1.00 (m, 2 H), 1.13-1.17 (m, 2 H), 1.96 (s, 3H), 2.00 (s, 3 H), 2.06-2.12 (m, 2 H), 3.13-3.18 (m, 1 H), 3.61 (t,J=7.3Hz, 2 H), 4.44 (t, J=77 Hz, 2 H), 5.54 (s, 2 H), 7.22 (t, J=7.3 Hz,1 H), 7.30 (t, J=7.3 Hz, 1 H), 7.56 (d, J=8.0 Hz, 1 H), 7.64 (d, J=8.1Hz, 1 H), 7.81 (d, J=6.0 Hz, 1 H), 8.61 (d, J=5.3 Hz, 1 H), 8.81 (s, 1H); MS m/e 459 (MH⁺).

EXAMPLE 61

Example 49 (0.050 g, 0.14 mmol) was combined withmethyl-2-hydroxyisobutyrate (0.018 g, 0.14 mmol), a catalytic amount of50% sodium methoxide in MeOH and diethyl carbonate (1 mL) in a sealedtube and the mixture was heated to 175° C. for 18 hours. The mixture wasconcentrated in vacuo and the residue was purified by preparative HPLC(gradient, 10% MeOH in H₂O with 0. 1% TFA to 90% MeOH in H₂O with 0.1%TFA) to give 0.018 g (21% yield) of the trifluoroacetic acid salt ofExample 61 as a glassy, colorless solid.

¹H NMR (DMSO-d₆) δ 0.99-1.01 (m, 2 H), 1.13-1.15 (m, 2 H), 1.52 (s, 6H), 2.11 (t, J=7.5 Hz, 2 H), 3.14-3.16 (m, 1 H), 3.60 (t, J=6.9 Hz, 2H), 4.46 (t, J=7.7 Hz, 2 H), 5.54 (s, 2 H), 7.23 (t, J=7.5 Hz, 1 H),7.31 (t, J=7.5 Hz, 1 H), 7.58 (d, J=8.0 Hz, 1 H), 7.69 (d, J=8.1 Hz, 1H), 7.81 (d, J=6.1 Hz, 1 H), 8.61 (s, 1 H), 8.81 (s, 1 H); MS m/e 475(MH⁺).

EXAMPLE 62

Example 49 (0.050 g, 0.14 mmol) was combined with N-chloroacetylurethane (0.024 g, 0.14 mmol), sodium bicarbonate (0.023g, 0.28 mmol)and anhydrous acetonitrile (2 mL) in a sealed tube. The mixture washeated to 140° C for 1 hour. The mixture was concentrated in vacuo andthe residue was purified by preparative HPLC (gradient, 10% MeOH in H₂Owith 0.1% TFA to 90% MeOH in H₂O with 0.1% TFA) to give 0.030 g (39%yield) of the trifluoroacetic acid salt of Example 62 as a glassy,colorless solid.

¹H NMR (DMSO-d₆) δ 0.98-1.01 (m, 2 H), 1.13-1.17 (m, 2 H), 2.00-2.06 (m,2 H), 3.13-3.18 (m, 1 H), 3.41 (t, J=6.8 Hz, 2 H), 4.00 (s, 2 H), 4.41(t, J=7.7 Hz, 2 H), 5.56 (s, 2 H), 7.22 (t, J=7.6 Hz, 1 H), 7.30 (t,J=7.3 Hz, 1 H), 7.56 (d, J=8.0 Hz, 1 H), 7.71 (d, J=8.1 Hz, 1 H), 7.81(d, J=6.3 Hz, 1 H), 8.60 (d, J=6.0 Hz, 1 H), 8.80 (s, 1 H), 10.77 (s, 1H); MS m/e 446 (MH⁺).

EXAMPLE 63

A mixture of Example 49 (100 mg, 0.27 mmol) and2-bromoethylchloroformate (51.7 mg, 0.27 mmol) was stirred at roomtemperature for 18 hours. The reaction mixture was filtered to removeinorganic impurities and the solid was washed with MeOH. The MeOHsolution was concentrated to give 126 mg (99% yield) of Example 63 as ahygroscopic solid.

¹H NMR (DMSO-d₆) δ 0.94 (bs, 2 H), 1.10 (d, J=5.4 Hz, 2 H), 1.21 (d,J=6.4 Hz, 2 H), 1.86-1.89 (m, 2 H), 3.09-3.11 (m, 1 H), .3.78-3.80 (m, 1H), 3.85-3.87 I (m,1H), 4.21-4.23 (m, 2 H), 4.35-4.37 (m, 2 H), 5.43 (s,2 H), 7.18 (t, J=7.7 Hz, 1 H), 7.25 (t, J=7.5 Hz, 1 H), 7.46-7.50 (m, 2H), 7.55-7.60 (m, 1 H), 8.37 (d, J=5.0 Hz, 1 H), 8.54 (s, 1 H); MS m/e469 (MH⁺).

EXAMPLE 64

A mixture of Example 63 (70 mg, 0.149 mmol) and lithiumbis(trimethylsilyl)amide (0.15 mL, 0.149 mmol) was stirred at reflux indioxane (15 mL) for 16 hours. The solvent was evaporated and the residuewas diluted with EtOAc, washed with H₂0, dried over Na₂SO₄, andevaporated to give 41 mg (63% yield) of Example 64.

¹H NMR (DMSO-d₆) δ 0.90-0.93 (m, 2 H), 1.01-1 .09 (m, 2 H), 1.92-1.98(m, 2 H), 2.98-3.03 (m, 1 H), 3.27 (t, J=6.9 Hz, 2 H), 3.55 (t, J=8.1Hz, 2 H), 4.27 (t, J=7.7 Hz, 2 H), 4.37 (t, J=7.7 Hz, 2 H), 5.40 (s, 2H), 7.17-7.20 (t, J=7.4 Hz, 1 H), 7.22-7.29 (m, 2 H), 7.56-7.62 (m, 2H), 8.25 (d, J=5.3 Hz, 1 H), 8.42 (s, 1 H); MS m/e 416 (MH⁺).

EXAMPLE 65

MS m/e 426 (MH⁺).

EXAMPLE 66

Example 65 was refluxed with hydrazine hydrate (5 mL) in MeOH (10 mL)for 1 hour. The solvent was evaporated and the oily residue was dilutedwith water and extracted with EtOAc. The combined organic extracts weredried over MgSO₄ and evaporated to give 467 mg (29% yield) of Example665.

¹H NMR (DMSO-d₆) δ 4.91 (q, J=9.3 Hz, 2 H), 5.38 (s, 2 H), 7.12-7.21 (m,2 H), 7.44 (d, J=5.3 Hz, 1 H), 7.45-7.50 (m, 1 H), 7.51-7.58 (m, 1 H),8.32 (d, J 5.3 Hz, 1 H), 8.38 (s, 1 H), 12.60 (s, 1 H); MS m/e 348(MH⁺).

EXAMPLE 67

¹H NMR (DMSO-d₆) δ 1.88-2.01 (m, 2 H), 2.01-2.13 (m, 2 H), 3.10-3.22 (m,2 H), 3.58-3.65 (m, 2 H), 3.70-3.79 (m, 2 H), 4.90-4.99 (m, 2 H),5.10-5.23 (m, 2 H), 5.95 (s, 2 H), 7.34 (t, J=7.6 Hz, 1 H), 7.43 (t,J=7.6 Hz, 1 H), 7.62 (d, J=8.0 Hz, 1 H), 7.98 (d, J=8.0 Hz, 1 H), 8.08(d, J=6.1 Hz, 1 H), 8.76 (d, J=6.4 Hz, 1 H), 9.18 (s, 1 H); IR (KBr,cm⁻¹) 3416, 2927, 1754, 1653, 1627, 1518, 1462, 1264, 1168, 1121, 831,755. MS m/e 445 (MH⁺).

EXAMPLE 68

¹H NMR (DMSO-d₆) δ 3.19-3.31 (m, 2 H), 3.56-3.63 (m, 2 H), 3.65-3.74 (m,2 H), 3.86-3.95 (m, 2 H), 4.00-4.09 (m, 2 H), 5.01 (t, J=7.5 Hz, 2 H),5.16 (q, J=9.0 Hz, 2 H), 5.93 (s, 2 H), 7.34 (t, J=7.6 Hz, 1 H), 7.43(t, J=7.6 Hz, 1 H), 7.61 (d, J=8.3 Hz, 1 H), 7.99 (d, J=7.9Hz, 1 H),8.08 (d, J=6.1 Hz, 1 H), 8.75 (d, J =6.4 Hz, 1 H), 9.18 (s, 1 H); IR(KBr, cm⁻¹) 3430, 1761, 1618, 1517, 1268, 1172, 823, 770; MS m/e 461(MH⁺).

EXAMPLE 69

¹H NMR (DMSO-d₆) δ 1.03-1.08 (m, 2 H), 1. 12-1.16 (m, 2 H), 2.01-2.17(m, 2 H), 2.21-2.31 (m, 2 H), 2.31-2.41 (m, 2 H), 3.21-3.35 (m, 3 H),3.40-50 (m, 1 H), 3.61-3.72 (m, 1 H), 4.45-4.51 (m, 2 H), 5.77(s, 2 H),7.41-7.48 (m, 2 H), 7.67 (d, J=8.1 Hz, 1 H), 7.85-7.88 (m, 2 H), 8.64(d, J=6.7 Hz, 1 H), 8.95 (s, 1 H); MS m/e 430 (MH⁺).

EXAMPLE 70

¹H NMR (CDCl₃) δ 1.14 (q, J=7.5 Hz, 2 H), 1.21 (q, J=6.4 Hz, 2 H),2.20-2.23 (m, 2 H), 3.07 (m, 1 H), 3.38 (s, 3 H), 3.38 (t, J=5.4 Hz, 2H), 4.56 (t, J=6.5 Hz, 2 H), 5.85 (s, 2 H), 7.40 (t, J=7.6 Hz, 1 H),7.45 (t, J=7.7 Hz, 11 H), 7.53-7.55 (m, 2 H), 7.88 (d, J=82 Hz, 1 H),8.38 (d, J=6.3 Hz, 1 H), 8.92 (s, 1 H); MS m/e 378 (MH⁺).

EXAMPLE 71

A solution of Example 70 (434 mg, 0.72 mmol) in CH₂Cl₂ (25 ML) wastreated with boron tribromide 1 M in CH₂Cl₂, 7.2 mL, 7.2 mmol). Thereaction mixture was stirred at room temperature for 40 minutes and thenwas quenched slowly with anhydrous MeOH. The solvent was evaporated andthe residue was diluted with MeOH and evaporated two more times.Purification by flash column chromatography (CH₂Cl₂/MeOH, 9: 1) gaveExample 71.

¹H NMR (DMSO-d₆) δ 1.07 (d, J=5.6 Hz, 2 H), 1.83 (t, J=6.2 Hz, 2 H),2.99 (t, J=3.2 Hz, 1 H), 3.17 (d, J=5.0 Hz, 1 H), 3.40 (t, J=5.4 Hz, 2H), 4.40 (t, J=6.8 Hz, 2 H), 4.75 (t, J=4.6, 1 H), 5.42 (s, 2 H), 7.16(t, J=7.5 Hz, 1 H), 7.24 (t, J=7.6 Hz, 1 H), 7.29 (d, J=4.8 Hz, 1 H),7.56 (d, J=8.1 Hz, 2 H), 8.25 (s, 1 H), 8.38 (s, 1 H); MS m/e 364 (MH⁺).

EXAMPLE 72

¹H NMR (CDCl₃) δ 0.99-1.03 (m, 2 H), 1.16-1.20 (m, 2 H), 1.65-1.69 (m,,2 H), 1.71-1.75 (m, 2 H), 2.00 (s, 3 H), 2.92-2.95 (m, 1 H), 4.03 (t,J=6.2 Hz, 2 H), 4.35 (t, J=7.3 Hz, 2 H), 5.37 (s, 2 H), 7.14 (d, J=5.0Hz, 1 H), 7.26-7.32 (m, 3 H), 7.56-7.77 (m, 1 H), 8.32 (d, J=5.4 Hz, 1H), 8.72 (s, 1 H); MS m/e 420 (MH⁺).

EXAMPLE 73

Example 72 (1.0 g, 2.48 mmol) and K₂CO₃ (1.03 g, 7.44 mmol) were stirredtogether in MeOH (5 mL) at room temperature for 1.5 hours. The mixturewas diluted with H₂O and extracted with CH₂Cl₂ (3×25 mL). The combinedextracts were washed with brine, dried over MgSO4, and evaporated. Theproduct was then recrystallized from MeOH to give 650 mg (70% yield) ofExample 73. Example 73 was converted to the HCl salt by treating asolution of 73 in MeOH with 4 N HCl in dioxane and then by evaporatingthe solvent.

¹H NMR (DMSO-d₆) δ 1.03-1.06 (m, 2 H), 1.12-1.16 (m, 2 H), 1.50-1.56 (m,2 H), 1.89-1.83 (m, 2 H), 3.13-3.17 (m, 1 H), 3.46 (t, J=6.3 Hz, 2 H),4.46 (t, J=7.5 Hz, 2 H), 5.70 (s, 2 H), 7.32 (t, J=7.3 Hz, 1 H), 7.39(t, J=7.5 Hz, 1 H), 7.62 (d, J=8.0 Hz, 1 H), 7.78 (d, J=7.8 Hz, 1 H),7.81 (d, J=6.4 Hz, 1 H), 8.61 (d, J =6.4 Hz, 1 H), 8.93 (s, 1 H); IR(KBr, cm⁻¹) 3350, 2907, 2443, 1736, 1516, 1421, 1172, 825; MS m/e 378(MH⁺). Anal. Calcd for C₂₉H₃₀N₄O₃•1.25 HCl: C, 59.63; H, 5.78; N, 16.56Found: C, 59.52; H, 5.88; N, 16.57.

EXAMPLE 74

Fmoc-L-valine (0.690 g, 2.00 mmol) was combined with oxalyl chloride(0.508 g, 4.00 mmol) and dichloromethane (10 mL), and the resultingsolution was stirred for 2 hours. The mixture was concentrated in vacuoto a yellow oil, which was then combined with Example 73 (0.252 g, 0.667mmol) in dry CH₃CN (15 mL). The resulting mixture was stirred for 72hours, then was diluted with H₂O (5 mL) and was concentrated in vacuo .The mixture was redissolved in EtOAc (50 mL) and the solution was washedsuccessively with saturated aqueous NaHCO₃ (3×10 mL) and brine (10 mL).The aqueous extracts were combined and back-extracted with EtOAc. Thecombined organic extracts were dried over anhydrous MgSO₄ andconcentrated in vacuo. Purification of the crude material by flashchromatography (CH₂Cl₂:MeOH, 25:1) gave 410 mg of Example 74 as anoff-white solid which was used immediately upon isolation.

EXAMPLE 75

A solution of Example 74 (410 mg) and piperidine (4 ml) in DMF (15 mL)was stirred for 18 hours. The mixture was concentrated in vacuo. Thecrude solid was redissolved in CH₂Cl₂ and filtered to remove insolubles.Purification of the crude product by flash chromatography (gradient,CH₂Cl₂:MeOH, 20:1 to 10:1) gave a 184 mg of an 85:15 mixture of Examples75 and 7.3. Repurification by preparative HPLC gave 284 mg (52% yield)of pure Example 75 as the tris-trifluoroacetic acid salt.

¹H NMR (DMSO) 8 0.93 (d, J=6.9 Hz, 3 H), 0.96 (d, J=6.9 Hz, 3 H),0.99-1.01 (m, 2 H), 1.13-1.17 (m, 2 H), 1.74-1.78 (m, 2 H), 1.86-1.92(m, 2 H), 2.11-2.17 (m, 1 H), 3.13-3.17 (m, 1 H), 3.93 (br s, 1 H),4.20-4.31 (m, 2 11), 4.44 (t, J=7.4 Hz, 2 H), 5.56 (s, 2 H), 7.23 (dd,J=7.5 Hz, 7.5 Hz, 1 H), 7.30 (dd, J=7.5 Hz, 7.5 Hz, 1 H), 7.57 (d, J=8.0Hz, 1 H), 7.67 (d, J=8.1 Hz, 1 H), 7.82 (d, J=6.3 Hz, 1 H), 8.37 (br s,2 H), 8.62 (d, J=5.7 Hz, 1 H), 8.83 (s, 1 H); MS m/e 477 (MH⁺).

EXAMPLE 76

¹H NMR (DMSO-d₆) δ 0.89-0.93 (m, 2 H), 1.06-1.08 (m, 2 H), 1.31-1.34 (m,2 H), 1.54-1.58 (m, 2 H), 1.58-1.66 (m, 2 H), 1.98 (s, 3 H), 2.97-3.00(m, 1 H), 3.96 (t, J=6.6 Hz, 2 H), 4,32 (t, J=7.5 Hz, 1 H), 5.39 (s, 2H), 7.16 (t, J=7.2 Hz, 1 H), 7.24 (t, J=7.0 Hz, 1 H), 7.29 (d, J=5.0 Hz,1 H), 7.58 (t, J=7.8 Hz, 2 H), 8.22 (bs, 1 H), 8.42 (bs, 1 H); MS m/e433 (MH⁺).

EXAMPLE 77

Example 76 (115 mg, 0.27 mmol) in 1 N HCl (20 mL) was heated to refluxfor 1 hour then concentrated. The oily residue was triturated withEtOAc/MeOH to give 106 mg (94% yield) of Example 77 106 mg (94% yield)as the HCl salt.

¹H NMR (DMSO-d₆) δ 1.04-1.10 (m, 2 H), 1.10-1.17 (m, 2 H), 1.42-1.53 (m,4 H), 1.85-1.91 (m, 2 H), 3.13-3.17 (m, 1 H), 3.40-3.50 (m, 2 H), 4.51(t, J=7.5 Hz, 2 H), 5.82 (s, 2 H), 7.43-7.46 (m, 1 H), 7.46-7.52 (m, 1H), 7.69 (d, J=8.0 Hz, 1 H), 7.85 (d, J=6.4 Hz, 1 H), 7.91 (d, J=8.0 Hz,1 H), 8.64 (d, J=6.4 Hz, 1 H), 8.97 (s, 1 H); MS m/e 391 (MH⁺).

EXAMPLE 78

Example 78 was prepared according to the general coupling procedureshown in Scheme I-C and was used immediately upon isolation.

EXAMPLE 79

To a solution of Example 79 (86 mg, 0.17 mmol) in THF (3 mL) was addedtetrabutylammonium fluoride (TBAF, 1 M in THF, 0.25 mL, 0.25 mmol). Thereaction mixture was stirred at room temperature for 18 hours at whichtime more tetrabutylammonium fluoride (TBAF, 1 M in THF, 0.50 mL, 0.50mmol) was added and stirring was continued at room temperature for anadditional 18 hours. Purification by flash column chromatography(CH₂Cl₂/MeOH, 9:1) gave Example 79.

¹H NMR (CDCl₃) δ 0.94-0.97 (m, 2 H), 1.07 (s, 6 H), 1.09-1.11 (m, 2 H),1.40 (t, J=3.6 Hz, 2 H), 1.67-1.70 (m, 1 H), 2.86-2.87 (m, 1 H), 4.25(t, J=7.7 Hz, 2 H), 5.31 (s, 2 H), 7.05 (d, J=5.3 Hz, 1 H), 7.18-7.21(m, 2 H), 7.27 (t, J=4.6 Hz, 1 H), 7.71 (t, J=4.6 Hz, 1 H), 8.24 (d,J=5.3 Hz, 1 H), 8.65 (s7 1 H); IR (KBr, cm⁻¹) 3373, 2966, 1720, 1609,1499, 1410, 913, 742; MS m/e 406 (MH⁺).

EXAMPLE 80

Example 80 was prepared according to the general coupling procedureshown in Scheme I-C and was used immediately upon isolation.

EXAMPLE 81

Example 81 was prepared according to the same deprotection procedure asExample 79 from Example 80.

¹H NMR (CDCl₃) δ 1.02-1.04 (m, 2 H), 1.16 (q, J=6.9 Hz, 2 HI), 1.32 (s,6 H), 1.81 (t, J=3.2 Hz, H), 2.49 (s, 1 H), 2.93 (m, 1 H), 4.45 (t,J=3.4 Hz, 2 H), 5.41 (s, 2 H), 7.14 (d, J=5.25 Hz, 1 H), 7.27-7.30 (m, 2H), 7.33 (d(1, J=2.5, 3.5 Hz, 1 H), 7.77 (dd, J=2.9, 3.1 Hz, 1 H), 8.34(d, J=5.3, 1 H), 8.77 (s, 1 H); MS m/e 392 (MH⁺).

EXAMPLE 82

¹H NMR (CDCl₃) δ 0.03 (s, 6 H), 0.80-0.86 (m, 2 H), 0.89 (s, 9 H),1.00-1.02 (m, 2 H), 1.15-1.17 (m, 2 H), 1.48-1.51 (m, 2 H), 1.77-1.86(m, 2 H), 2.05 (t, J=7.4 Hz, 2 H), 2.89-2.97 (m, 1 H), 4.29 (t, J=7.4Hz, 2 H), 5.35 (s, 2 H), 7.10 (d, J=5.2 Hz, 1 H), 7.24-7.26 (m, 2 H),7.31-7.33 (m, 1 H), 7.74-7.77 (m, 1 H), 8.31 (d, J=5.2 Hz, 1 H), 8.69(s, 1 H); MS m/e 518 (MH⁺).

EXAMPLE 83

Example 83 was prepared from Example 82 according to the samedeprotection procedure described for Example 79.

¹H NMR (DMSO-d₆) δ 0.91-1.05 (m, 4 H), 1.13-1.22 (m, 2 H), 1.77-1.84 (m,2 H), 2.27 (q, J=7.4 Hz, 2 H), 2.39 (t=6.8 Hz, 2 H), 2.89-2.95 (m, 1 H),4.23 (t, J =7.7Hz, 2 H), 5.27 (s, 2 H), 7.03 (d, J=5.1 Hz, 1 H),7.24-7.31 (m, 2 H), 7.34 (dd, J=1.9, 6.4 Hz, 1 H), 7.66 (dd, J=1.4, 7.1Hz, 1 H), 8.23 (d, J=5.2 Hz, I H), 8.60 (s, 1 H); IR (KBr, cm⁻¹) 3392,2938, 1721, 1609, 1499, 1410, 913, 743; MS m/e 404 (MH⁺).

EXAMPLE 84

¹H NMR (CDCl₃) δ 0.05 (t, J=5.8 Hz, 2 H), 0.14 (s, 6 H), 0.63 (t, J=6.1Hz, 2 H), 0.90 (s, 9 H), 1.00-1.03 (m, 2 H), 1.13-1.17 (m, 2 H), 1.86(t, J=6.6 Hz, 2 H), 2.89-2.92 (m, 1 H), 4.61 (t, J=6.6 Hz, 2 H), 5.42(s, 2 H), 7.12 (d, J=4.9 Hz, 1 H), 7.22-7.24 (m, 2 H), 7.38-7.40 (m, 1H), 7.72-7.74 (m, 1 H), 8.32 (d, J=5.5 Hz, 1 H), 8.66 (s, 1 H); MS m/e504 (MH⁺).

EXAMPLE 85

Example 85 was prepared from Example 84 according to the samedeprotection procedure described for Example 79.

¹H NMR (DMSO-d₆) δ 0.10 (q, J=4.8 Hz, 2 H), 0.49 (q, J=4.91 Hz, 2 H),0.90-0.94 (m, 2 H), 1.04-1.07 (m, 2 H), 1.85 (t, J=7.0 Hz, 2 H), 2.99(m, 1 H), 4.54 (t, J=7.0 Hz, 2 H), 5. 42 (s, 1 H), 5.46 (s, 2 H), 7.16(dt, J=1.0, 7.6 Hz, 1 H), 7.23 (dt, J=1.0, 7.6 Hz, 1 H), 7.28 (d, J=5.2Hz, 1 H), 7.54 (dd, J=8.0, 23.0 Hz, 2 H), 8.25 (d, J=5.25 Hz. 1 H), 8.39(s, 1 H); MS m/e 390 (MH⁺).

EXAMPLE 86

To a solution of oxalyl chloride (326 mg, 2.57 mmol) in, CH₂Cl₂ (5 mL)cooled to −78° C. with a dry ice/acetone bath was added a solution ofDMSO (268 mg, 3.42 mmol) in CH₂Cl₂ (10 mL) slowly over 15 minutes. Afterstirring for 10 minutes, a solution of Example 71 (622 mg, 1.71 mmol) inCH₂Cl₂ (5 mL) was slowly added to the reaction mixture. The reaction wasmonitored for completion by thin layer chromatography and LC/MS. Thesolution became cloudy upon completion and the reaction was quenched at31 78° C. by adding triethylamine (693 mg, 6.85 mmol). The solutionbecame clear and was then warmed to room temperature. The reactionmixture was diluted with more CH₂Cl₂, washed with water and brine, driedover MgSO₄, and evaporated. Purification by flash column chromatography(gradient, EtOAc/MeOH, 10:1 to 3:1) gave 185 mg (19% yield) of Example86 which was used immediately upon isolation.

EXAMPLE 87

Example 87 was prepared according to the procedure described in J. Med.Chem., 1996, 39, 2411-2421 by Yu, K.-L. et al. using aldehyde :86:

A fresh solution of anhydrous 1 M tetrabutylammonium fluoride in THF wasprepared according to the procedure described by Cox et al in J. OrganicChemistry, 1984, 49, 3219-3220.

To a solution of Example 86 (150 mg, 0.42 mmol) in TIFF (10 mL) wasadded trimethyl(trifluoromethyl) silane (0.5M in THF, 1.25 mL, 0.62mmol) followed by a catalytic amount of tetrabutylammonium fluoride(TBAF, 1M in THF, 8 μL) at 0° C. The reaction mixture was stirred at 0°C. for 1.5 hours and then warmed to room temperature. Additionaltrimethyl(triflucoromethyl) silane (0.5M in THF, 1.05 mL, 0.53 mmol) andTBAF (1M in THF, 8 μL) were added to push the reaction towardcompletion. The reaction was quenched with excess TBAF (1M in THF, 2.88mL, 2.88 mmol) and the reaction mixture was allowed to stir for 18hours. The solvent was evaporated and the residue was purified by flashcolumn chromatography (gradient, straight EtOAc to EtOAc/MeOH, 5:1) togive 106 mg (59% yield) of Example 87.

¹H NMR (CD₃OD) δ 0.98-1.07 (m, 2 H), 1.08-1.16 (m, 1 H), 1.89-1.97 (m, 1H), 2.08-2.14 (m, 1 H), 2.99-3.04 (m, 2 H), 3.91-3.95 (m, 1 H),4.53-4.63 (m, 2 H), 5.46-5.55 (m, 2 H), 7.25-7.28 (m, 1 H), 7.33 (dt,J=0.9, 7.8 Hz, 1 H), 7.40 (d, J 5.5 Hz, 1 H), 7.58 (d, J=8.1 Hz, 2 H),8.26 (d, J=5.4 Hz, 1 H), 8.30 (s, 1 H); IR (KBr, cm¹) 3422, 1723, 1613,1504, 1412, 1173, 1131, 745; MS m/e 432 (MH⁺).

EXAMPLE 88

¹H NMR (CDCl₃) δ 0.92-0.95 (m, 2 H), 1.03-1.07 (m, 2 H), 2.81-2.85 (m, 1H), 3.53 (t, J=4.8 Hz, 2 H), 4.07 (t, J=4.8 Hz, 2 H), 5.36 (s, 2 H),5.69 (s, 2 H), 7.04 (d, J=5.5 Hz, 1 H), 7.19-7.23 (m, 3 H), 7.33-7.39(m, 3 H), 7.48-7.51 (m, 1 H), 7.70-7.72 (m, 1 H), 7.86 (d, J=8.3 Hz, 1H), 8.22 (d, J=5.2 Hz, 1 H), 8.52 (s, 1 H); MS m/e 484 (MH⁺).

EXAMPLE 89

To a solution of Example 88 (30.5 mg, 0.06 mmol) in MeOH (1 mL) wasadded ammonia (2 M in MeOH, 1 mL). The reaction mixture was stirred atroom temperature for 16 hours. The solvent was concentrated.Purification by preparative HPLC (gradient, 10% MeOH in H₂O with 0. 1%TFA to 90% MeOH in H₂O with 0.1% TFA) followed by treatment with excess4 N HCl in dioxane gave Example 89 as the HCl salt.

¹H NMR (CD₃OD) 61.11-1.17 (m, 2 H), 1.21-1.26 (m, 2 H), 3.13-3.20 (m, 1H), 3.59-3.66 (m, 2 H), 3.72-3.77 (m, 2 H), 5.98 (s, 2 H), 6.11 (s, 2H), 7.62 (t, J7.4 Hz, 1 H), 7.66 (t, J=7.6 Hz, 1 H), 7.78 (d, J=8.0 Hz,1 H), 7.92 (d, J=4.2 Hz, 1 H), 8.04 (d, J=8.0 Hz, 1 H), 8.58 (d, J=3.9Hz, 1 H), 8.89 (s, 1 H); MS m/e 380 (MH⁺).

EXAMPLE 90

MS m/e 510 (MH⁺).

EXAMPLE 91

Example 91 was prepared from Example 90 according to the same proceduredescribed for Example 71.

¹H NMR (DMSO-d₆) δ 1.53-1.59 (m, 2 H), 1.87-1.92 (m, 2 H), 3.47 (t,J=6.4 Hz, 2 H), 4.54 (t, J=7.6 Hz, 2 H), 5.17 (q, J=9.0 Hz, 2 H), 5.89(s, 2 H), 7.44 (t, J=7.6 Hz, 1 H), 7.51 (t, J=7.6 Hz, 1 H), 7.70 (d,J=8.1 Hz, 1 H), 7.91 (d, J=8.2 Hz, 1 H), 8. 10 (d, J=6.4 Hz, 1 H), 8.80(d, J=6.5 Hz, 1 H), 9.1 1 (s, 1 H). MS m/e 420 (MH⁺).

EXAMPLE 92

Example 92 was prepared from Example 91 according to the same proceduredescribed for Example 86.

¹H NMR (CDCl₃) δ 1.94-1.99 (m, 2 H), 2.59 (t, J=6.7Hz, 2 H), 4.31-4.35(m, 2 H), 4.53 (q, J=8.5 Hz, 2 H), 5.46 (s, 2 H), 7.07 (d, J=6.4 Hz, 1H), 7.27-7.34 (m, 2 H), 7.44 (d, J=7.5 Hz, 1 H), 8.78 (dd, J=0.9, 7.2Hz, 1 H), 8.39 (d, J=5.4 Hz, 1 H), 8.85 (s, 1 H), 9.78 (s, 1 H); MS m/e418 (MH⁺).

EXAMPLE 93

Example 93 was prepared from Example 92 according to the same proceduredescribed for Example 87.

¹H NMR (CD₃OD) δ 1.60-1.73 (m, 1 H), 1.78-1.90 (m, 1 H), 2.00-2.14 (m, 2H), 3.96-4.01 (m, 1 H), 4.53 (t, J=7.8 Hz, 2 H), 4.94 (q, J=8.9 Hz, 2H), 5.69 (s, 2 H), 7.34-7.44 (m, 2 H), 7.60 (d, J=7.8 Hz, 1 H), 7.68 (d,J=7.5 Hz, 1 H), 7.92 (d, J=6.3 Hz, 1 H), 8.60 (d, J=5.7 Hz, 1 H), 8.82(s, 1 H); MS m/e 488 (MH⁺).

EXAMPLE 94

¹H NMR (CDCl₃) δ 1.68-1.73 (m, 2 H), 1.74-1.80 m,2 H), 1.99 (s, 3 H),2.54 (s, 3 H), 4.04-6.3 Hz, 2 H), 4.35 (t, J=7.5 Hz, 2 H), 5.48 (s, 2H), 6.97 (s, I H), 7.27-7.35 (m, 3 H), 7.78-7.80 (m, 1 H), 8.00 (d,3J=5.4 Hz, 1 H), 8.46 (d, 3J 5.4 Hz, 1 H), 8.86 (s, 1 H); IR (KBr, cm⁻¹)3421, 1727, 1599, 1527, 1484, 1457, 1257, 75 1; MS m/e 461 (MH⁺); Anal.Calcd for C₂₄H₂₄N₆O₄•2.0 H₂O: C, 58.06; H, 5.68; N, 16.93 Found: C,58.36; H, 5.55; N, 16.97.

EXAMPLE 95

Example 95 was prepared from Example 94 according to the same proceduredescribed for Example 73.

¹H NMR (CDCl₃) δ 1.60-1.66 (m, 2 H), 1.79-1.85 (m, 2 H), 3.65 (t, J=6.1Hz, 2 H), 4.35 (t, J=7.9 Hz, 2 H), 5.50 (s, 2 H), 6.95 (s, 1 H),7.28-7.36 (m, 3 H), 7.77-7.79 (m, 1 H), 8.00 (d, J=5.4 Hz, 1 H), 8.45(d, J=5.4 Hz, 1 H), 8.87 (s, 1 H); IR (KBr, cm⁻¹) 3309, 1728, 1602,1528, 1483, 1452, 1385, 1171, 827, 739; MS m/e 419 (MH⁺).

EXAMPLE 96

Example 96 was prepared via synthesis of the acetate intermediateaccording to the same procedure described for Example 72 followedimmediately by deprotection of the alcohol according to the sameprocedure described for Example 73.

¹H NMR (CDCl₃) δ 1.61-1.67 (m, 2 H), 1.79-1.85 (m, 2 H), 1.90-2.05 (m, 2H), 2.43-2.49 (m, 2 H), 2.81-2.89 (m, 2 H), 3.68 (t, J=6.0 Hz, 2 H),4.34 (t, J=7.8 Hz, 2 H), 4.85-4.92 (m, 1 H), 5.43 (s, 2 H), 7.22-7.35(m, 4 H), 7.75-7.77 (m, 1 H), 8.33 (d, J=5.5 Hz, 1 H), 8.82 (s, 1 H); MSm/e 392 (MH⁺); Anal. Calcd for C₂₂H₂₅N₅O₂•0.5 H₂O: C, 65.98; H, 6.54; N,17.49 Found: C, 65.71; H, 6.62; N, 17.37.

EXAMPLE 97

Example 97 was prepared via synthesis of the acetate intermediateaccording to the same procedure described for Example 72 followedimmediately by deprotection of the alcohol according to the sameprocedure described for Example 73.

¹H NMR (CDCl₃) δ 1.61-1.67 (m, 2 H), 1.75-1.83 (m, 4 H), 1.95-2.02 (mi,2 H), 2.05-2.11 (m, 4 H), 3.68 (t, J=6.0 Hz, 2 H), 4.35 (t, J=7.9 Hz, 2H), 4.82-4.89 (mi, 1 H), 5.43 (s, 2 H), 7.04 (d, J=5.5 Hz, 1 H),7.22-7.30 (m, 2 H), 7.32-7.35 (m, 1 H), 7.76-7.78 (mi, 1 H), 8.30 (d,J=5.5 Hz, 1 H), 8.82 (s, 1 H); IR (KBr, cm⁻¹) 3272, 2945, 2870, 1710,1607, 1496, 1395, 742; MS m/e 406 (MH⁺); Anal. Calcd for C₂₃H₂₈N₅O₂: C,67.95; H, 6.94; N, 17.22 Found: C, 67.78; H, 6.72; N, 16.92.

EXAMPLE 98

Example 98 was prepared via synthesis of the acetate intermediateaccording to the same procedure described for Example 72 followedimmediately by deprotection of the alcohol according to the sameprocedure described for Example 73.

¹H NMR (DMSO-d₆) δ 1.43-1.48 (m, 2 H), 1.66-1.69 (m, 2 H), 2.18 (s, 3H), 3.37-3.41 (m, 2 H), 4.35 (t, J=7.3 Hz, 2 H), 4.47 (t, J=5.1 Hz, 1H), 5.25 (s, 1 H), 5.44 (s, 2 H), 5.46 (d, J=1.0 Hz, 1 H), 7.17-7.27 (m,3 H), 7.57-7.60 (m, 2 H), 8.25 (d, J=5.2 Hz, 1 H), 8.48 (s, 1 H); MS m/e378 (MH⁺).

EXAMPLE 99

Example 99 was prepared from Example 98 according to the same proceduredescribed for Example 17.

¹H NMR (DMSO-d₆) δ 1.44-1.48 (m, 2 H), 1.65-1.68 (m, 2 H), 3.38-3.42 (m,2 H), 4.34 (t, J=7.5 Hz, 2 H), 4.47 (t, J=5.1 Hz, 1H), 5.38 (s, 1 H),7.07 (d, J=5.2 Hz, 1 H), 7.19 (t, J=7.0 Hz, 1 H), 7.23 (t, J=7.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 1 H), 8.15 (d, J=5.1 Hz, 1 H), 8.34 (s, 1 H),11.59 (s, 1 H); MS m/e 338 (MH⁺).

EXAMPLE 100

¹H NMR (CD₃OD) δ 1.54-1.60 (m, 2 H), 1.86-1.92 (m, 2 H), 3.52 (t, J=6.2Hz, 2 H), 4.45 (t, J=7.7 Hz, 2 H), 5.20 (s, 1 H), 5.65 (d, J=6.8 Hz, 2H), 7.21-7.32 (m, 4 H), 7.34-7.37 (m, 3 H), 7.52-7.55 (m, 1 H), 7.63 (t,J=8.4 Hz, 1 H), 8.37 (d, J=6.5 Hz, 1 H), 8.68 (s, 1 H); MS m/e 428(MH⁺).

EXAMPLE 101

To a solution of Example 99 (34 mg, 0.1 mmol) and4-dimethylaminopyridine (DMAP, 2.0 mg, 0.02 mmol) in pyridine (1 ml) wasadded acetic anhydride (22 mg, 0.22 mmol) at room temperature. Afterstirring for 12 hours, the reaction mixture was diluted with EtOAc (10ml) and washed twice with H₂O and brine. The combined organic extractswere dried over MgSO₄, and concentrated. The residue was purified byflash column chromatagraphy (CH₂Cl₂/MeOH, 20:1) to yield 35 mg(82%yield) of Example 101 as a white solid.

¹H NMR (CDCl₃) δ 1.69-1.82 (m, 4 H), 2.00 (s, 3 H), 2.80 (s, 3 H), 4.06(t, J=6.2 Hz, 2 H), 4.34 (t, J=6.6 Hz, 2 H), 5.39 (s, 2 H), 7.26-7.32(m, 3 H), 7.75-7.78 (m, 1 H), 8.03 (d, J=5.1 Hz, 1 H), 8.42 (d, J=3.2Hz, 1 H), 8.82 (s, 1 H); MS m/e 422 (MH⁺).

EXAMPLE 102

¹H NMR (DMSO-d₆) δ 0.64-0.68 (m, 2 H), 0.81-0.86 (m, 2 H), 1.28-1.37 (m,4 1 5 H), 1.72 (s, 3 H), 2.27 (s, 3 H), 2.73-2.77 (m, 1 H), 3.72 (t,J=6.2 Hz, 2 H), 4.07 (t, J=7.1 Hz, 2 H), 5.14 (s, 2 H), 6.76 (d, J=7.3Hz, 1 H), 6.90 (t, J=7.7 Hz, I H), 7.03 (d, J=5.25 Hz, 1 H), 7.13 (d,J=8.1 Hz, 1 H), 8.00 (d, J=5.25 Hz, I H), 8.23 (s, 1 H); MS m/e 434(MH⁺).

EXAMPLE 103

Example 103 was prepared from Example 102 according to the sameprocedure described for Example 73.

¹H NMR (DMSO-d₆) δ 0.90-0.95 (m, 2 H), 1.05-1.10 (m, 2 H), 1.35-1.41 (m,2 H), 1.50-1.55 (m, 2 H), 2.51 (s, 3 H), 2.97-3.00 (m, 1 H), 4.27 (t,J=7.5 Hz, 2 H), 4.43 (t, J=5.0Hz, 2 H), 5.38 (s, 2 H), 7.00 (d, J=7.2Hz,1 H), 7.13 (t, J=7.7 Hz, 1 H), 7.27 (d, J=5.2 Hz, 1 H), 7.34 (d, J=8.1Hz, 1 H), 8.23 (d, J=5.2 Hz, 1 H), 8.45 (s, 1 H); MS m/e 392 (MH⁺).

EXAMPLE 104

¹H NMR (CDCl₃) δ 1.00-1.02 (m, 2 H), 1.14-1.18 (m, 2 H), 1.22 (t, J=7.1Hz, 3 H), 2.38 (t, J=7.15 Hz, 2 H), 2.91-2.96 (m, 1 H), 4.10 (q,J=7.2Hz, 2 H), 4.38 (t, J=7.6 Hz, 2 H), 5.37 (s, 2 H), 7.16 (d, J=5.4Hz, 1 H), 7.24-7.30 (m, 4 H), 7.39 (d, J=6.6 Hz, 1 H), 7.75 (d, J=7.0Hz, 1 H), 8.33 (d, J=5.3 Hz, 1 H), 8.71 (s, 1 H); MS m/e 419 (MH⁺).

EXAMPLE 105

A mixture of Example 104 (346 mg, 0.83 mmol) and aqueous sodiumhydroxide (1N, 4.1 mL, 4.13 mmol) were stirred in MeOH (5 mL) for 14hours at room temperature. The mixture was neutralized with HCl followedby flash column chromatography to give Example 105.

¹H NMR (CDCl₃) δ 1.13-1.16 (m, 2 H), 1.22-1.25 (m, 2 H), 2.36-2.41 (m, 4H), 3.09-3.12 (m, 1 H), 4.56 (t, J=6.6 Hz, 2 H), 5.91 (s, 2 H),7.47-7.57 (m, 4 H), 7.93 (d, J=7.6 Hz, 1 H), 8.3 7 (d, J=6.4 Hz, 1 H),9.17 (s, 1 H); MS m/e 392 (MH⁺).

EXAMPLE 106

A solution of Example 105 (0.23 g, 0.50 mmol), 1-hydroxybenzotriazolehydrate (HOBT, 75 mg, 0.54 mmol), trifluoroethylamine hydrocloride (75mg, 0.54 mmol), and N-methylmorpholine (0.21 g, 2.16 mmol) was stirredat room temperature for 30 minutes until a homogeneous solutionresulted. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(EDAC ,103 mg, 0.54 mmol) was added and the mixture was stirred for 12hours. The solution was concentrated and the residue dissolved in EtOAcand washed with water and saturated NaHCO₃, dried over MgSO₄ andconcentrated to give 35 mg (18% yield) of Example 106 as a white solid.

¹H NMR (DMSO-d₆) δ 0.89-0.93 (m, 2 H), 1.06-1.08 (m, 2 H), 1.86-1.89 (m,2 H), 2.27-2.30 (m, 2 H), 2.98-3.00 (m, 1 H), 4.31-4.34 (m, 2 H), 5.40(s, 2 H), 7.18-7.23 (m, 1 H), 7.25-7.29 (m, 2 H), 7.57-7.58 (m, 2 H)8.25-8.26 (m, 1 H) 8.41 (s, 1 H), 8.57-8.60 (m, 1 H); MS m/e 472 (MH⁺).

EXAMPLE 107

Example 104 (100 mg, 0.24 mmol) in neat cyclopropylamine (1.22 g, 21.40mmol) was heated at 105° C. in a sealed tube for 18 hours. The reactionmixture was concentrated and the residue was purified by flash columnchromatography to give Example 107.

¹H NMR (CDCl₃) δ 0.45-0.48 (m, 2 H), 0.74-0.78 (m, 2 H), 0.98-1.03 (m, 2H), 1.14-1.18 (m, 2 H), 1.99-2.04 (m, 2 H), 2.20 (t, J=6.9Hz, 2 H),2.67-2.70 (m, 1 H), 2.92-2.96 (m, 1 H), 4.37 (t, J=7.6 Hz, 2 H), 5.36(s, 2 H), 7.14 (d, J=5.2 Hz, 1 H0, 7.24-7.29 (m, 2 H), 7.44 (d, J=7.0Hz, 1 H), 7.75 (d, J=7.4 Hz, 1 H), 8.34 (d, J=5.2 Hz, 1 H), 8.70 (s, 1H); MS m/e 431 (MH⁺).

EXAMPLE 108

Example 104 (52 mg, 0.12 mmol) in methylamine (40% aqueous solution, 4mL) was heated at 120° C. in a sealed tube for 18 hours. The solvent wasevaporated and the residue purified by flash column chromatography togive Example 108 as a 2:1 mixture of cis/trans rotomers.

¹H NMR (CDCl₃) δ 0.96-1.00 (m, 2 H), 1.08-1.14 (m, 2 H), 1.94-2.02 (m, 2H), 2.19-2.23 (m, 2 H), 2.75 (d, J=6.0 Hz, 3 H), 2.88-2.92 (m, 1 H),4.29-4.36 (m, 2 H), 5.33, 5.34 (s, 2 H), 7.07, 7.10 (d, J6.5 Hz, 1 H),7.11-7.27 (m, 2 H), 7.66-7.71 (m, 1 H), 8.25, 8.28 (d, J=6.7 Hz, 1 H),8.57, 8.63 (s, 1 H); MS m/e 405 (MH⁺).

EXAMPLE 109

A mixture of Example 47 (500 mg, 1.64 mmol) and methyl vinyl ketone (574mg, 8.2 mmol) in EtOH (10 ml) was heated to reflux for 8 hours. Aftercooling, the solid was collected by filtration to give 378 mg (61%) ofExample 109 as a white solid.

¹H NMR (CDCl₃) δ 1.01-1.05 (m, 2 H), 1.15-1.19 (m, 2 H), 2.10 (s, 3 H),2.91-2.96 (m, 3 H), 4.60 (t, J=6.4 Hz, 2 H), 5.53 (s, 2 H), 7.17 (d,J=5.4 Hz, 1 H), 7.24-7.30 (m, 2 H), 7.32-7.34 (m, 1 H), 7.73-7.75 (m, 1H), 8.34 (d, J=5.4 Hz, 1 H), 8.69 (s, 1 H); MS m/e 376 (MH⁺).

EXAMPLE 110

A mixture of Example 109 (37 mg, 0.10 mmol) and hydroxylaminehydrochloride (7.6 mg, 0.11 mmol) in MeOH (2 ml) was heated to refluxfor 2 hours, diluted with EtOAc (20 ml) and washed with aqueoussaturated NaHCO₃. The organic layer was separated, dried over MgSO₄, andevaporated to give 34 mg (87% yield) of Example 110 as white solid.

¹H NMR (CDCl₃) δ 1.01-1.05 (m, 2 H), 1.15-1.19 (m, 2 H), 1.89 (s, 3 H),2.64 (t, J=6.5 Hz, 2 H), 2.89-2.92 (m, 1 H), 4.58 (t, J=6.6 Hz, 2 H),5.41 (s, 2 H), 7.12-7.31 (m, 4 H), 7.69-7.72 (m, 1 H), 8.29 (d, J=4.8Hz, 1 H), 8.57 (s, 1 H); MS m/e 391 (MH⁺).

EXAMPLE 111

¹H NMR (CDCl₃) δ 1.03-1.07 (m, 2 H), 1.16-1.20 (m, 2 H), 2.86 (t, J=6.5Hz, 2 H), 2.93-2.97 (m, 1 H), 4.78 (t, J=6.5 Hz, 2 H), 5.43 (s, 2 H),7.18 (d, J=5.4 Hz, 1 H), 7.30-7.36 (m, 3 H), 7.81-7.82 (m, 1 H), 8.36(d, J=5.4 Hz, 1 H), 8.84 (s, 1 H); IR (KBr, cm⁻¹) 3405, 1709, 1605,1500, 1466, 1455, 1411, 1179, 750; MS m/e 359 (MH⁺); Anal. Calcd forC₂₀H₁₈N₆O•0.5H₂O: C, 65.38; H, 5.21; N, 22.87 Found: C, 65.49; H, 5.09;N, 22.41.

EXAMPLE 112

¹H NMR (CD₃OD) δ 3.11 (t, J=6.6 Hz, 2 H), 4.72-4.82 (m, 4 H), 5.59 (s, 2H), 7.28-7.38 (m, 3 H), 7.60-7.64 (m, 2 H), 8.29 (d, J=5.7 Hz, 1 H),8.53 (s, 1 H).

EXAMPLE 113

¹H NMR (CDCl₃) δ 1.90-2.10 (m, 4 H), 2.43-2.49 (m, 4 H), 2.80-2.89 (m, 2H), 4.48 (t, J=7.4 Hz, 2 H), 4.84-4.90 (m, 1 H), 5.40 (s, 2 H),7.21-7.38 (m, 4 H), 7.77-7.79 (m, 1 H), 8.34 (d, J=5.5 Hz, 1 H), 8.82(s, 1 H); MS m/e 387 (MH⁺); Anal. Calcd for C₂₂H₂₂N₆O: C, 68.37; H,5.73; N, 21.74 Found: C, 68.21; H, 5.83; N, 21.71.

EXAMPLE 114

A mixture of Example 26 (610 mg, 1.62 mmol), hydroxylamine hydrochloride(408 mg, 5.87 mmol) and potassium carbonate (450 mg, 3.24 mmol) werestirred in a EtOH and H20 (2:1 ratio mixture, 60 mL) at 80° C. for 18hours. The solvent was evaporated and the residue was diluted with H20to dissolve inorganic salts. The white solid was filtered and driedunder high vacuum to give 545 mg (83% yield) of Example 114 as a whitesolid.

¹H NMR (DMSO-d₆) δ 0.90-0.93 (m, 2 H), 1.05-1.07 (m, 2 H), 1.87-1.90 (m,2 H), 2.06 (t, J=7.5 Hz, 2 H), 3.00-3.02 (m, 1 H), 4.32 (t, J=7.6 Hz, 2H), 5.41 (s, 2 H), 5.46 (bs, 2 H), 7.17 (t, J=7.3 Hz, 1 H), 7.24 (t,J=7.3 Hz, 1 H), 7.29 (d, J =5.2 Hz, 1 H), 7.57 (d, J=7.9 Hz, 1 H), 7.60(d, J=8.0 Hz, 1 H), 8.25 (d, J=5.2 Hz, 1 H), 8.40 (s, 1 H), 8.84 (s, 1H).

EXAMPLE 115

Example 114 (210 mg, 0.52 mmol) was treated with phosgene (20% intoluene, 2.56 g, 5.2 mmol) and heated to reflux for 12 hours. Additionalphosgene (20% in toluene 2.56 g, 5.2 mmol) was added and the mixtureheated to reflux for another 6 hours. The solution was concentrated tohalf volume and the white solid was isolated by filtration to give 138mg (62% yield) of Example 115.

¹H NMR (DMSO-d₆) δ 1.05-1.05 (bs, 2 H), 1.15-1.16 (m, 2 H), 2.21-2.26(m, 2 H), 2.71-2.75 (m, 2 H), 3.15-3.17 (m, 1 H), 4.51-4.58 (m, 2 H),5.74-5.78 (m, 2 H), 7.37-7.40 (m, 1 H), 7.45-7.47 (m, 1 H), 7.63-7.66(m, 1 H), 7.84-7.89 (m, 2 H), 8.64 (d, J=6.4 Hz, 1 H), 8.92-8.95 (m, 1H); MS m/e 432 (MH⁺).

EXAMPLE 116

A mixture of the Example 114 (100 mg, 0.24 mmol) was heated to reflux intriethylorthoformate (2.5 mL) for 12 hours. The solution wasconcentrated and the residue purified by preparative HPLC (C 18,gradient 0-100% MeOH/H₂O with 0. 1% trifluoroacetic acid). The productwas treated with 4 N HCl in dioxane and concentrated to give 38 mg (35%yield) of the Example 116 as the hydrochloride salt.

¹H NMR (DMSO-d₆) δ 0.97-1.02 (m, 2 H), 1.10-1.16 (m, 2 H), 2.25-2.35 (m,2 H), 2.95-2.99 (m, 2 H), 3.14-3.16 (m, 1 H), 4.55-4.65 (m, 2 H), 5.77(s, 2 H), 7.39-7.41 (m, 1 H), 7.46-7.48 (m, 1 H), 7.66-7.68 (m, 1 H),7.84-7.90 (m, 2 H), 8.64 (d, J=6.1 Hz, 1 H), 8.94 (s, 1 H), 9.57 (s, 1H); MS m/e 416 (MH⁺).

EXAMPLE 117

A mixture of Example 114 (250 mg, 0.62 mmol) was heated to reflux withcyclopropanecarbonyl chloride (354 mg, 3.39 mmol) and pyridine (2 mL)for 12 hours. The solution was concentrated and the residue purified bypreparative HPLC (C18, gradient 0-100% MeOH/H₂O with 0.1%trifluoroacetic acid). The product was treated with 4N HCl in dioxaneand concentrated to give 80 mg (28% yield) of Example 117 as thehydrochloride salt.

¹H NMR (DMSO-d₆) δ 1.04-1.06 (m, 4H), 1.13-1.15 (m, 2 H), 1.20-1.23 (m,2 H), 2.21-2.31 (m, 2 H), 2.83-2.85 (m, 2 H), .3.11-3.19 (m, 1 H),3.65-3.75 (m, 1 H), 4.55-4.57 (m, 2 H), 5.75 (s, 2 H), 7.35-7.42 (m, 1H), 7.45-7.52 (m, 1 H), 7.65 (d, J=8.1 Hz, 1 H), 7.83-7.85 (m, 2 H),8.62 (d, J=8.1 Hz, 1 H), 8.92 (s, 1 H); MS m/e 456 (MH⁺).

EXAMPLE 118

Example 118 was prepared according to the same procedure described forExample 117 using trifluoroacetic anhydride.

¹H NMR (DMSO-d₆) δ 1.02-1.05 (m, 2 H), 1.12-1.16 (m, 2 H), 2.31-2.34 (m,2 H), 3.10 (t, J=7.3 Hz, 2 H), 3.13-3.16 (m, 1 H), 4.59 (t, J=7.6 Hz, 2H), 5.74 (s, 2 H), 7.38 (t, J=7.8 Hz, 1 H), 7.45 (t, J=7.4 Hz, 1 H),7.65 (d, J=8.0 Hz, 1 H), 7.85 (d, J=7.7 Hz, 1 H), 7.88 (d, J=8.2 Hz, 1H), 8.63 (d, J=8.2 Hz, 1 H), 8.94 (s, 1 H); MS m/e 483 (MH⁺).

EXAMPLE 119

Example 119 was prepared according to the same procedure described forExample 117 using acetic anhydride.

¹H NMR (DMSO-d₆) δ 1.01-1.05 (m, 2 H), 1.13-1.15 (m, 2 H), 2.24-2.28 (m,2 H), 2.55 (s, 3 H), 2.85-2.88 (m, 1 H), 3.15-3.18 (m, 2 H), 4.55 (t,J7.4 Hz, 2 H), 5.71 (bs, 2 H), 7.29-7.38 (m, 1 H), 7.40-7.47 (m, 1 H),7.64 (d, J=7.4 Hz, 1 H), 7.80-7.86 (m, 2 H), 8.63 (d, J=6.4 Hz, 1 H),8.90 (s, 1 H); MS m/e 430 (MH⁺).

EXAMPLE 120

¹H NMR (DMSO-d₆) δ 2.06-2.12 (m, 2 H), 2.63 (t, J=7.3 Hz, 2 H), 4.42 (t,J 7.5 Hz, 2 H), 4.92 (q, J=9.3 Hz, 2 H), 5.51 (s, 2 H), 7.18 (t,J=7.5Hz, 1 H), 7.27 (t, J=7.5 Hz, 1 H), 7.45 (d, J=5.2 Hz, 1 H), 7.56(d, J=8.0 Hz, 1 H), 7.62 (d, J=8.2 Hz, 1 H), 8.33 (d, J=5.5 Hz, 1 H),8.51 (s, 1 H).

EXAMPLE 121

Example 121 was prepared from Example 120 according to the sameprocedure as Example 114.

¹H NMR (DMSO-d₆) δ 1.91-1.98 (m, 2 H), 2.30 (t, J=7.0Hz, 2 H), 4.37 (t,J=7.7Hz, 2 H), 4.91 (q, J=9.1 Hz, 2 H), 5.51 (s, 2 H), 7.15-7.18 (m, 1H), 7.23-7.27 (m, 1 H), 7.44 (d, J=5.2 Hz, 1 H), 7.55 (d, J=7.9 Hz, 1H), 7.61 (d, J=8.0 Hz, 1 H), 8.06 (bs, 1 H), 8.31 (d, J=5.2 Hz, 2 H),8.46 (s, 1 H), 9.48 (s, 1 H); MS m/e 448 (MH⁺).

EXAMPLE 122

¹H NMR (CDCl₃) δ 1.00-1.06 (m, 2 H), 1.15-1.19 (m, 2 H), 2.14-2.19 (m, 2H), 2.91-2.95 (m, 1 H), 3.55 (t, J=6.0 Hz, 2 H), 4.52 (t, J=6.7 Hz, 2H), 5.40 (s, 2 H), 7.14-7.15 (m, 1 H), 7.26-7.32 (m, 2 H), 7.39-7.40 (m,1 H), 7.76-7.78 (m, 1 H), 8.34 (d, J=5.0 Hz, 1 H), 8.72 (s, 1 H); MS m/e382 (MH⁺); Anal. Calcd for C₂₀H₂₀ClN₅O: C, 62.90; H, 5.27; N, 18.34Found: C, 62.58; H, 5.17; N, 18.18.

EXAMPLE 123

A mixture of Example 122 (38 mg, 0.10 mmol) and sodium azide (20 mg,0.30 mmol) in DMF (2 ml) was heated to 70° C. for 2 hours. The finalsolution was diluted with EtOAc (10 ml) and washed with H₂O (3×10 ml)and brine. The combined organic extracts were dried over MgSO₄,concentrated, and purified by flash chromatography, (gradient,CH₂Cl₂/MeOH, 40:1 to 20:1) to yield 33 mg (85% yield) of Example 123 asa white solid.

¹H NMR (CDCl₃) δ 1.00-1.05 (m, 2 H), 1.13-1.19 (m, 2 H), 1.91-1.97 (m, 2H), 2.90-2.94 (m, 1 H), 3.35 (t, J=6.3 Hz, 2 H), 4.43 (t, J=7.2 Hz, 2H), 5.37 (s, 2 H), 7.12 (d, J=5.2 Hz, 1 H), 7.26-7.30 (m, 2 H),7.33-7.35 (m,1 H), 7.77 (d, J=7.2 Hz, 1 H), 8.32 (d, J=5.0 Hz, 1 H),8.72 (s, 1 H); MS m/e 388 (MH⁺); Anal. Calcd for C₂₀H₂₀N₈O: C, 61.84; H,5.19; N, 28.84 Found: C, 61.59; H, 5.27; N, 28.50.

EXAMPLE 124

¹H NMR (CDCl₃) δ 1.02-1.05 (m, 2 H), 1.15-1.19 (m, 2 H), 2.90-2.95 (m, 1H), 3.77 (t, J=6.0Hz, 2 H), 4.76 (t, J=6.1 Hz, 2 H), 5.44 (s, 2 H), 7.14(d, J=5.2 Hz, 1 H), 7.28-7.32 (m, 3 H), 7.78-7.80 (m, 1 H), 8.34 (d,J=4.8 Hz, 1 H), 8.77 (s, 1 H); MS m/e 368 (MH⁺).

EXAMPLE 125

Example 125 was prepared from Example 124 according to the sameprocedure described for Example 123.

¹H NMR (CDCl₃) δ 1.01-1.06 (m, 2 H), 1.16-1.20 (m, 2 H), 2.92-2.96 (m, 1H), 3.70 (t, J=6.0Hz, 2 H), 4.54 (t, J=6.1 Hz, 2 H), 5.43 (s, 2 H), 7.15(d, J=5.2 Hz, 1 H), 7.29-7.32 (m, 3 H), 7.78-7.81 (m, 1 H), 8.34 (d,J=4.8 Hz, 1 H), 8.79 (s,1H); MS m/e 375 (MH⁺); Anal. Calcd forC₁₉H₁₈N₈O•0.25 H₂O: C, 60.23; H, 4.92; N, 29.57 Found: C, 60.30; H,4.85; N, 29.44.

EXAMPLE 126

¹H NMR (CDCl₃) δ 1.00-1.04 (m, 2 H), 1. 16-1.20 (m, 2 H), 1.79-1.81 (m,4 H), 2.92-2.96 (m, 1 H), 3.49-3.50 (m, 2 H), 4.35 (s, 2 H), 5.37 (s, 2H), 7.13 (d, J=5.2 Hz, 1 H), 7.26-7.33 (m, 3 H), 7.76-7.79 (m, 1 H),8.83 (d, J=5.2 Hz, 1 H), 8.72 (s, 1 H); MS m/e 396 (MH⁺); Anal. Calcdfor C₂₁H₂₂ClN₅O•0.20 H₂O: C, 63.14; H, 5.64; N, 17.53 Found: C, 62.74;H, 5.54; N, 17.57.

EXAMPLE 127

Example 127 was prepared from Example 126 according to the sameprocedure described for Example 123.

¹H NMR (CDCl₃) δ 0.99-1.02 (m, 2 H), 1. 15-1.19 (m, 2 H), 1.58-1.63 (m,2 H), 1.69-1 .75 (m, 2 H), 2.90-2.95 (m, 1 H), 3.27 (t, J=6.5 Hz, 2 H),4.32 (t, J=7.3 Hz, 2 H), 5.35 (s, 2 H), 7.12 (d, J=5.0 Hz, 1 H),7.25-7.31 (m, 3 H), 7.76-7.77 (m, 1 H), 8.32 (d, J=4.8 Hz, 1 H), 8.71(s, 1 H); MS m/e 403 (MH⁺).

EXAMPLE 128

¹H NMR (DMSO-d₆) δ 0.91-0.94 (m, 2 H), 1.04-1.09 (m, 2 H), 1.20 (t,J=7.5 Hz, 3 H), 2.06-2.13 (m, 2 H), 2.98-3.02 (m, 1 H), 3.11 (q, J=7.5Hz, 2 H), 3.16-3.21 (m, 2 H), 4.86 (t, J=7.6 Hz, 2 H), 5.42 (s, 2 H),7.18-7.21 (m, 1 H), 7.26-7.30 (m, 2 H), 7.59 (d, J=8.0 Hz, 1 H), 7.64(d, J=8.1 Hz, 1 H), 8.26 (d, J=5.3 Hz, 1 H), 8.44 (s, 1 H); IR (KBr,cm⁻¹) 3421, 1610, 1706, 1500, 1458, 1409, 1298, 1131, 751; MS m/e 440(MH⁺); Anal. Calcd for C₂₂H₂₅N₅O₃S•2 H₂O: C, 55.56; H, 6.15; N, 14.73Found: C, 55.29; H, 5.89; N, 14.59.

EXAMPLE 129

¹H NMR (DMSO-d₆) δ 1.21 (t, J=7.4 Hz, 3 H), 2.14-2.16 (m, 2 H), 3.13 (q,J=7.4 Hz, 2 H), 3.22 (t, J=7.5 Hz, 2 H), 4.50 (t, J=7.5 Hz, 2 H), 4.91(q, J=9.3 Hz, 2 H), 5.53 (s, 2 H), 7.19 (t, J=7.7 Hz, 1 H), 7.28 (t,J=7.7 Hz, 1 H), 7.46 (d, J=5.3 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 7.65(d, J=8.0 Hz, 1 H), 8.33 (d, J=5.0 Hz, 1 H), 8.52 (s, 1 H); IR(Br,cm⁻¹)3430, 2945, 1726, 1615, 1500, 1411, 1266, 1170, 1125, 745; MSm/e 482 (MH⁺); Anal. Calcd for C₂₁H₂₂F₃N₅O₃S•0.25 H₂O: C, 51.90; H,4.67; N, 14.41 Found: C, 51.69; H, 4.74; N, 14.17.

EXAMPLE 130

¹H NMR (DMSO-d₆) δ 0.92-0.93 (m, 2 H), 1.05-1.07 (m, 2 H), 1.23 (d,J=6.8 Hz, 6 H), 2.06-2.12 (m, 2 H), 2.98-3.02 (m, 1 H), 3.16-3.20 (m, 2H), 3.28-3.30 (m, 1 H), 4.49 (t, J=7.6 Hz, 2 H), 5.42 (s, 2 H), 7.21 (t,J=7.1 Hz, 1 H), 7.26-7.30 (m, 2 H), 7.59 (d, J=8.0 Hz, 1 H), 7.64 (d,J=8.0 Hz, 1 H), 8.25 (d, J=5.2 Hz, 1 H), 8.44 (s, 1 H); IR (KBr, cm⁻¹)2926, 1720, 1604, 1498, 1471, 1420, 1267, 1126, 746; MS m/e 454 (MH⁺);Anal. Calcd for C₂₃H₂₇N₅O₃S•0.7 H₂O: C, 59.26; H, 6.14; N, 15.02 Found:C, 59.58; H, 6.10; N, 14.63.

EXAMPLE 131

¹H NMR (CDCl₃) δ 2.03-2.17 (m, 2 H), 3.53 (t, J=6.2 Hz, 2 H), 4.45-4.54(m, 4 H), 5.44 (s, 2 H), 7.01 (d, J=5.1 Hz, 1 H), 7.24-7.32 (m, 2 H),7.37-7.41 (m, 2 H), 7.73-7.78 (m, 1 H), 8.36 (d, J=5.4 Hz, 1 H), 8.79(s, 1 H); MS m/e 424 (MH⁺).

EXAMPLE 132

To a volume of DMF (1 0 mL) saturated with excess methanethiol at −78°C. was added sodium hydride (60% suspension in mineral oil, 56 mg, 1.39mmol). The mixture was warmed to 0° C. and stirred for 30 minutes. Themixture was then added to a solution of Example 131 (3 94 mg, 0. 93mmol) in DMF (2 mL) and was stirred at 0° C. for 30 minutes. The solventwas evaporated under high vacuum. The residue was neutralized withconcentrated HCl and the solvent was evaporated. The residue was dilutedwith CH₂Cl₂ and was washed with saturated aqueous NaHCO₃ and H₂O, driedover MgSO₄, and evaporated. Purification by flash column chromatography(gradient, straight EtOAc to EtOAc/MeOH, 10:1) gave 374 mg (93% yield)of Example 132. Example 132 (200 mg, 0.46 mmol) was converted to the HClsalt by treating a solution of Example 132 in MeOH with excess 4N HCl indioxane and then by evaporating the solvent to give 223 mg (96% yield).

¹H NMR (CD₃OD) δ 2.14 (s, 3 H), 2.30-2.39 (m, 2 H), 2.70 (t, J=6.6 Hz, 2H), 25 4.78 (t, J=7.4 Hz, 2 H), 5.01 (q, J=8.7 Hz, 2 H), 6.05 (s, 2 H),7.62-7.75 (m, 2 H), 7.76 (d, J=7.5 Hz, 1 H), 7.99-8.04 (m, 2 H), 8.71(d, J=6.6 Hz, 1 H), 9.09 (s, 1 H); IR (KBr, cm⁻¹) 3412, 2762, 1760,1655, 1624, 1519, 1264, 1169, 1119, 834, 752; MS m/e 436 (MH⁺).

EXAMPLE 133

A mixture of Example 132 (174 mg, 0.40 mmol) and sodium periodate (94mg, 0.44 mmol) in H₂O (5 mL) was stirred at 0° C. To this mixture wasadded DMF (2 mL) in order to dissolve the solids and the resultingsolution was stirred at room temperature for 48 hours The reactionmixture was diluted with CH₂Cl₂, washed with water, dried over MgSO₄ andevaporated. Purification by flash column chromatography (gradient,straight EtOAc to EtOAc/MeOH, 5:1) gave 145 mg (81% yield) of Example133 which was converted to the HCl salt by treating a solution ofExample 133 in MeOH with 4N HCl in dioxane and then by evaporating thesolvent.

¹H NMR (CD₃OD) δ 2.02-2.15 (m, 2 H), 2.53 (s, 3 H), 2.68 (t, J=7.4 Hz, 2H), 4.43-4.56 (m, 4 H), 5.43 (s, 2 H), 7.02 (d, J=5.1 Hz, 1 H),7.26-7.31 (m, 2 H), 7.35-7.38 (m, 1 H), 7.74-7.77 (m, 1 H), 8.35 (d,J=5.4 Hz, 1 H), 8.79 (s, 1 H); IR(KBr,cm¹)3412,2854, 1760, 1656, 1624,1519, 1264, 1169, 1120, 753; MS m/e 452 (MH⁺); Anal. Calcd forC₂₀H₂₀F₃N₅O₂S•2HClH₂O: C, 44.29; H, 4.46; N, 12.91 Found: C, 44.08; H,4.93; N, 11.54.

EXAMPLE 135

¹H NMR (DMSO-d₆) δ 1.73-1.92 (m, 2 H), 2.13-2.16 (m, 2 H), 2.31-2.33 (m,2 H), 2.79-2.83 (m, 2 H), 3.00 (s, 3 H), 3.24 (t, J=7.7 Hz, 2 H), 4.49(t, J=7.4 Hz, 2 H), 4.85-4.92 (m, 1 H), 5.44 (s, 2 H), 7.19-7.20 (m, 1H), 7.26-7.27 (m, 1H), 7.49 (d, J=5.3 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H),7.63 (d, J=8.05 Hz, 1 H), 8.25 (d, J=5.3 Hz, 1 H), 8.46 (s, 1 H); MS m/e440 (MH⁺); Anal. Calcd for C₂₂H₂₅N₅O₃S: C, 60.11; H, 5.73; N, 15.93Found: C, 60.09; H, 5.76; N, 15.89.

EXAMPLE 136

¹H NMR (DMSO-d₆) δ 2.12-2.18 (m, 5 H), 3.00 (s, 3 H), 3.24 (t, J=7.6 Hz,2 H), 4.51 (t, J=7.6 Hz, 2 H), 5.45-5.48 (m, 3 H), 7.19-7.28 (m, 3 H),7.59 (d, J=8.0 Hz, 1 H), 7.64 (d, J=8.1 Hz, 1 H), 8.26 (d, J=5.3 Hz, 1H), 8.52 (s, 1 H); MS m/e 426 (MH⁺).

EXAMPLE 137

Example 137 was prepared from Example 136 according to the sameprocedure described for Example 17.

¹H NMR (DMSO-d₆) δ 2.12-2.16 (m, 2 H), 3.00 (s, 3 H), 3.24 (t, J=7.6 Hz,2 H), 4.49 (t, J=7.6 Hz, 2 H), 5.41 (s, 2 H), 7.08 (d, J=7.0 Hz, 1 H),7.17-7.20 (m, I H), 7.25-7.29 (m, 1 H), 7.58 (d, J=8.0 Hz, 1 H), 7.63(d, J=8.0 Hz, 1 H), 8.17 (d, J=5.2 Hz, 1 H), 8.39 (s, 1 H); MS m/e 386(MH⁺).

EXAMPLE 138

¹H NMR (CDCl₃) δ 2.16-2.22 (m, 2 H), 2.91 (s, 3 H), 3.09 (t, J=7.3 Hz, 2H), 3.88 (t, J=5.9Hz, 2 H), 4.26 (t, J=6.0Hz, 2 H), 4.51 (t, J=7.6Hz, 2H), 5.44 (s, 2 H), 7.20 (d, J=5.3 Hz, 1 H), 7.28-7.34 (m, 2 H),7.37-7.39 (m, 1 H), 7.78-7.80 (m, 1 H), 8.36 (d, J=5 .1 Hz, 1 H), 8.78(s, 1 H); MS m/e 448 (MH⁺).

EXAMPLE 139

Example 139 was prepared from Example 138 according to the sameprocedure described for Example 123.

¹H NMR (CDCl₃) δ 2.18-2.24 (m, 2 H), 2.91 (s, 3 H), 3.09 (t, J=7.3 Hz, 2H), 3.73 (t, J=5.9 Hz, 2 H), 4.08 (t, J=6.0 Hz, 2 H), 4.51 (t, J=7.6 Hz,2 H), 5.44 (s, 2 H), 7.07 (d, J=5.3 Hz, 1 H), 7.26-7.33 (m, 2 H),7.33-7.38 (m, 1 H), 7.77-7.79 (m, 1 H), 8.36 (d, J=5.1 Hz, 1 H), 8.79(s, 1 H); MS m/e 455 (MH⁺); Anal. Calcd for C₂₀H₂₂N₈O₃S•0.5 H₂O: C,51.83; H, 5.00; N, 24.17 Found: C, 51.85; H, 4.82; N, 23.97.

EXAMPLE 140

¹H NMR (DMSO-d₆) δ 0.89-0.92 (m, 1 H), 1.06-1.08 (m, 1 H), 1.65-1.72 (m,2 H), 2.96-2.99 (m, 1 H), 4.35-4.50 (m, 3 H), 5.40 (s, 2 H), 7.17-7.20(m, 1 H), 7.24-7.29 (m, 2 H), 7.59 (d, J=8.2 Hz, 2 H), 8.25 (d, J=5.1Hz, 1 H), 8.41 (s, 1 H); MS m/e 380 (MH⁺).

EXAMPLE 141

¹H NMR (DMSO-d₆) δ 1.67-1.77 (m, 4 H), 4.37-4.42 (m, 3 H), 4.49-4.51 (m,1 H),4.92 (q, J9.2 Hz, 2 H), 5.50 (s, 2 H), 7.18 (t, J7.6Hz, 1 H), 7.26(t, J=7.7, 1 H), 7.44 (d, J=4.3, 1 H), 7.57-7.61 (m, 2 H), 8.30-8.33(bs, 1 H), 8.49-8.51 (bs, 1 H); MS m/e 422 (MH^(t)).

EXAMPLE 142

¹H NMR (DMSO-d₆) δ 1.03-1.04 (m, 2 H), 1.14-1.16 (m, 2 H), 2.06-2.08 (m,2 H), 3.11-3.18 (m, 1 H), 4.52-4.55 (m, 4 H), 5.70 (s, 2 H), 7.34-7.39(m, 1 H), 7.43-7.47 (m, 1 H), 7.63 (d, J=8.1 Hz, 1 H), 7.84 (d, J=6.4Hz, 2 H), 8.63 (d, J =6.4 Hz, 1 H), 8.92 (s, 1 H); MS m/e 416 (MH⁺).

EXAMPLE 143

¹H NMR (DMSO-d₆) δ 1.84-1.87 (m, 2 H), 4.50-4.53 (m, 4 H), 5.14 (q,J=9.0 Hz, 2 H), 5.74 (s, 2 H), 7.30-7.32 (m, 1 H), 7.37-7.40 (m, 1 H),7.60 (d, J=8.2 Hz, 1 H), 7.80 (d, J=8.0, 1 H), 8.05 (d, J=6.2 Hz, 1 H),8.74 (d, J=6.3 Hz, 1 H), 9.04 (s, 1 H); MS m/e 458 (MH⁺).

EXAMPLE 144

¹H NMR (DMSO-d₆) δ 1.85-1.92 (m, 6 H), 2.18 (t, J=8.1 Hz, 2 H),2.36-2.41 (m, 2 H), 2.34 (t, J=7.3 Hz, 2 H), 3.88 (t, J=7.3 Hz, 2 H),4.43 (t, J=7.6 Hz, 2 H), 5.46 (s, 2 H), 7.19 (t, J=7.0 Hz, 1 H), 7.27(t, J=7.0 Hz, 1 H), 7.38 (d, J=5.5 Hz, 1 H), 7.58 (d, J=8.0 Hz, 1 H),7.64 (d, J=7.9 Hz, 1 H), 8.26 (d, J=5.2 Hz, 1 H), 8.46 (s, 1 H); MS m/e501 (MH⁺).

EXAMPLE 145

Example 145 was prepared according to the general coupling proceduredescribed in Scheme I-C with 4-bromo-1,1,2-trifluoro-I-butene which gavean elimination product.

¹H NMR (DMSO-d₆) δ 0.96-0.99 (m, 2 H), 1.14-1.16 (m, 2 H), 3.15-3.17 (m,1 H), 5.53 (s, 2 H), 5.72 (d, J=11.6 Hz, 1 H), 5.81 (d, J=17.4 Hz, 1 H),6.77-6.86 (m, 1 H), 7.34-7.42 (m, 2 H), 7.54 (d, J=7.9 Hz, 1 H), 7.69(d, J=7.9 Hz, 1 H), 7.85 (d, J=6.4 Hz, 1 H), 8.64 (d, J=6.1 Hz, 1 H),8.90 (s, 1 H); MS m/e 394 (MH⁺).

EXAMPLE 146

¹H NMR (DMSO-d₆) δ 0.64-0.66 (m, 2 H), 0.97-0.98 (m, 2 H), 2.77-2.78 (m,I H), 5.40 (s, 2 H), 5.59 (s, 2 H), 6.77-6.81 (m, 2 H), 6.94 (t, J=8.9Hz, 2 H), 7.15 (d, J=5.2 Hz, 1 H), 7.21-7.23 (m, 2 H), 7.40-7.42 (m, 1H), 7.68-7.70 (m, 1H), 8.20 (d, J=5.2 Hz, 1 H), 8.31 (s, 1 H);MS m/e 413(MH⁺).

EXAMPLE 147

¹H NMR (DMSO-d₆) δ 4.74-4.79 (m, 2 H), 5.49 (s, 2 H), 5.60 (s, 2 H),6.96-7.04 (m9 4 H), 7.17-7.25 (m, 2 H), 7.36 (d, J=5.2 Hz, 1 H), 7.48(d, J=7.3 Hz, 1 H), 7.65 (d, J=6.7 Hz, 1 H), 8.28 (d, J=5.5 Hz, 1 H),8.36 (s, 1 H); MS m/e 456 (MH⁺).

EXAMPLE 148

¹H NMR (DMSO-d₆) δ 0.53-0.56 (m, 2 H), 0.92-0.96 (m, 2 H), 2.66-2.69 (m,1 H), 5.41 (s, 2 H), 5.71 (s, 2 H), 6.83 (d, J=8.2 Hz, 2 H), 7.06 (d,J=5.2 Hz, 1 H), 7.23-7.25 (m, 2 H), 7.40-7.42 (m, 3 H), 7.72-7.74 (m, 1H), 8.18 (d, J=5.1 Hz, 1 H), 8.30 (s, 1 H); MS m/e 464 (MH⁺).

EXAMPLE 149

¹H NMR (DMSO-d₆) δ 4.68-4.70 (m, 2 H), 5.49 (s, 2 H), 5.74 (s, 2 H),7.04 (d, J =8.1 Hz, 2 H), 7.22-7.23 (m, 2H), 7.31 (d, J=5.3 Hz, 1 H),7.40-7.50 (m, 1H), 7.51 (d, J=8.2 Hz, 2 H), 7.64-7.70 (m, 1 H), 8.25(d,J=5.2 Hz, 1 H), 8.38 (s, 1 H); MS m/e 464 (MH⁺).

EXAMPLE 150

¹H NMR (DMSO-d₆) δ 0.76-0.77 (m, 2 H), 1.05-1.07 (m, 2 H), 2.92-2.96 (m,1 H), 3.56 (s, 3 H), 5.56 (s, 2 H), 5.81 (s, 2 H), 7.14 (d, J=8.3 Hz, 2H), 7.26-7.28 (m, 2 H), 7.47-7.49 (m, 1 H), 7.68-7.71 (m, 2 H), 7.77 (d,J=8.4 Hz, 2 H), 8.58 (d, J=6.4 Hz, 1 H), 8.72 (s, 1 H); MS m/e 474(MH⁺).

EXAMPLE 151

¹H NMR (DMSO-d₆) δ 3.20 (s, 3 H), 4.95-5.02 (m, 2 H), 5.66 (s, 2 H),5.84 (s, 2 H), 5.56 (s, 2 H), 5.81 (s, 2 H), 7.26-7.29 (m, 2 H), 7.34(d, J=8.3 Hz, 2 H), 7.51-7.53 (m, 1 H), 7.64-7.66 (m, 1 H), 7.85 (d,J=8.4 Hz, 2 H), 7.99 (d, J=6.3 Hz, 1 H), 8.71 (d, J=6.4 Hz, 1 H), 8.93(s, 1 H); MS m/e 516 (MH⁺).

EXAMPLE 152

¹H NMR (DMSO-d₆) δ 0.78-0.81 (m, 2 H), 1.05-1.09 (m, 2 H), 2.95-2.98 (m,1 H), 5.60 (s, 2 H), 5.95 (s, 2 H), 7.30 (dd, J=3.0, 6.1 Hz, 2 H), 7.39(d, J=8.6 Hz, 2 H), 7.48-7.51 (m, 2 H), 7.71 (dd, J=3.0, 6.1 Hz, 2 H),7.73 (d, J=6.4 Hz, 1 H), 8.04 (d, J=8.6 Hz, 1 H), 8.60 (d, J=6.4 Hz, 1H), 8.82 (s, 1 H); MS m/e 528 (MH⁺).

EXAMPLE 153

¹H NMR (DMSO-d₆) δ 0.68-0.71 (m, 2 H), 0.96-1.00 (m, 2 H), 2.79-2.82 (m,1 H), 5.49 (s, 2 H), 5.69 (s, 2 H), 7.02 (d, J=7.9 Hz, 1 H), 7.16-7.21(m, 4 H), 7.43-7.45 (m, 1 H), 7.59-7.65 (m, 2 H), 8.21 (d, J=5.0 Hz, 1H), 8.24 (d, J=3.9 Hz, 1 H), 8.35 (s,1 H);

EXAMPLE 154

¹H NMR (CD₃OD) δ 1.16-1.20 (m, 2 H), 1.21-1.27 (m, 2 H), 2.44-2.48 (m, 1H), 2.51-2.56 (m, 1 H), 3.18-3.22 (m, 1 H), 3.32-3.34 (m, 1 H),3.74-3.78 (m, 1 H), 4.73-4.78 (m, 1 H), 4.81-4.89 (m, 2 H), 6.01 (d, 2H), 7.63-7.67 (m, 1 H), 7.68-7.72 (m, 1 H), 7.79 (d, J=8.2 Hz, 1 H),7.94 (d, J=6.4 Hz, 1 H), 8.02 (d, J=8.3 Hz, 1 H), 8.61 (d, J=6.4 Hz, 1H), 8.96 (s, 1 H); MS m/e 419 (MH⁺).

EXAMPLE 155

¹H NMR (CDCl₃) δ 1.00-1.03 (m, 2 H), 1.08-1.12 (m, 2 H), 1.68-1.74 (m, 2H), 1.84-1.90 (m, 2 H), 2.06 (s, 3 H), 3.47-3.51 (m, 2 H), 4.09 (t,J=6.3 Hz, 2 H), 4.46 (t, J=7.5 Hz, 2 H), 5.42 (s, 2 H), 6.99-7.01 (m, 1H), 7.20-7.27 (m, 2 H), 7.33-7.37 (m, 2 H), 7.76 (d, J=7.6 Hz, 1 H),8.06-8.07 (m, 1 H); MS m/e 420 (MH⁺).

EXAMPLE 156

Example 156 was prepared from Example 155 according to the sameprocedure described for Example 73.

¹H NMR (CD₃OD) δ 1.01-1.04 (m, 2 H), 1.13-1.68 (m, 2 H), 1.63-1.68 (m, 2H), 1.94-2.01 (m, 2 H), 2.68 (s, 3 H), 3.01-3.04 (m, 1 H), 3.60 (t,J=6.2 Hz, 2 H), 4.69 (t, J=7.9 Hz, 2 H), 5.73 (s, 2 H), 7.19-7.22 (m, 1H), 7.63-7.69 (m, 3 H), 7.74-7.76 (m, 1 H), 7.98 (d, J=7.6 Hz, 1 H),8.03-8.04 (m, 1 H); MS m/e 478 (MH⁺); Anal. Calcd forC₂₁H₂₃N₅O₂•CH₄O₃S•0.75 H₂O: C, 54.21; H, 5.85; N, 14.22 Found: C, 54.25;H, 5.90; N, 14.38.

EXAMPLE 157

¹H NMR (CDCl₃) δ 0.98-1.01 (m, 2 H), 1.07-1.10 (m, 2 H), 1.65-1.71 (m, 2H), 1.84-1.90 (m, 2 H), 2.86-2.90 (m, 1 H), 3.47-3.51 (m, 2 H), 4.43 (t,J=7.6 Hz, 2 H), 4.47 (s, 2 H), 5.37 (s, 2 H), 6.97-6.99 (m, 1 H),7.18-7.33 (m, 9 H), 7.72-7.74 (m, 1 H), 8.03-8.06 (m, 1 H); MS m/e 468(MH⁺).

EXAMPLE 158

To a suspension of Example 156 (52 mg, 0.14 mmol) and sodium hydride(6.6 mg, 0.16 mmol) in DMF (2 mL) was added N,N-dimethylcarbamoylchloride (16.2 mg, 0.15 mmol) at 0° C. The resulting mixture was stirredat room temperature for 12 hours. The mixture was diluted with EtOAc andwashed with water. The organic extracts were dried with MgSO₄ andevaporated. The residue was purified by flash chromatography (gradient,CH₂Cl₂/MeOH, 40:1 to 20: 1) to give 35 mg (56% yield) of Example 158 asa off-white solid.

¹H NMR (CDCl₃) δ 1.00-1.03 (m, 2 H), 1.08-1.12 (m, 2 H), 1.68-1.74 (m, 2H), 1.84-1.90 (m, 2 H), 2.84 (s, 3 H), 2.90-2.93 (m, 4 H), 4.09 (t,J=6.3 Hz, 2 H), 4.46 (t, J=7.5 Hz, 2 H), 5.42 (s, 2 H), 6.99-7.01 (m, 1H), 7.20-7.27 (m, 2 H), 7.33-7.37 (m, 2 H), 7.76 (d, J=7.6 Hz, 1 H),8.06-8.07 (m, 1 H); MS m/e 449 (MH⁺).

EXAMPLE 159

Example 159 was prepared via synthesis of the acetate intermediateaccording to the same procedure described for Example 72 followedimmediately by deprotection of the alcohol according to the sameprocedure described for Example 73.

¹H NMR (d₆-DMSO) δ 1.44-1.54 (m, 2 H), 1.77-1.86 (m, 2 H), 3.41 (t,J=6.3 Hz, 2 H), 4.46 (t, J=7.2 Hz, 2 H), 5.53 (s, 2 H), 7.21 (dd, J=5.3,8.0 Hz, 1 H), 7.28-7.40 (m, 2 H), 7.59 (d, J=7.8 Hz, 1 H), 7.76 (d,J=7.8 Hz, 2 H), 7.84 (t, J=57.6 Hz, 1 H), 8.10 (d, J=4.8 Hz, 1 H); IR(KBr, cm¹) 3275, 2941, 1751, 1623, 1606, 1466, 2503, 1031, 772, 746; MSm/e 388 (MH⁺); Anal. Calcd for C₁₉H₁₉F₂N₅O₂•0.25 H₂O: C, 58.23; H, 5.02;N, 17.87 Found: C, 58.42; H, 4.79; N, 17.64.

EXAMPLE 160

¹H NMR (CD₃OD) δ 1.02-1.05 (m, 2 H), 1.11-1.17 (m, 2 H), 2.32-2.38 (m, 2H), 2.68 (s, 3 H), 2.71 (t, J=7.2 Hz, 2 H), 3.01-3.05 (m, 1 H), 5.79 (s,2 H), 7.20-7.22 (m, 1 H), 7.64-7.76 (m, 4 H), 7.99-8.05 (m, 2 H); MS m/e373 (MH⁺); Anal. Calcd for C₁₉H₁₈N₈O•1.0 H₂O•1.0 CH₄SO₃: C, 54.31; H,5.39; N, 17.27 Found: C, 54.58; H, 5.37; N, 17.37.

EXAMPLE 161

¹H NMR (CD₃OD) δ 2.37-2.40 (m, 2 H), 2.68 (s, 3 H), 2.73 (t, J=7.3 Hz, 2H), 4.82 (t, J=7.6 Hz, 2 H), 5.80 (s, 2 H), 7.26-7.28 (m, 1 H), 7.62 (t,J=58.0 Hz, 1 H), 7.65-7.79 (m, 4 H), 8.00 (d, J=8.3 Hz, 1 H), 8.17 (dd,J=1.3, 5.3 Hz, 1 H); IR (KBr, cm⁻¹) 3449, 3064, 2953, 1758, 1466, 1410,1230, 1156, 1048, 771, 551; MS m/e 383 (MH⁺); Anal. Calcd forC₁₉H₁₆F₂N₆O•0.5 H₂O•1.0 CH₃SO₃H: C, 49.28; H, 4.34; N, 17.24 Found: C,49.36; H, 4.42; N, 16.95.

EXAMPLE 162

¹H NMR (CD₃OD) δ 1.35 (t, J=7.5 Hz, 3 H), 2.50-2.57 (m, 2 H), 3.15 (q,J=7.5 Hz, 2 H), 3.35 (t, J=7.2 Hz, 2 H), 4.86 (t, J=7.2 Hz, 2 H), 5.77(s, 2 H), 7.24-7.27 (m, 1 H), 7.59-7.68 (m, 3 H), 7.62 (t, J=58.0 Hz, 1H), 7.71 (d, J=8.3 Hz, 1 H), 7.78 (d, J=7.8 Hz, 1 H), 7.98 (d, J=8.1 Hz,1 H), 8.16 (d, J=5.2 Hz, 1 H); MS m/e 450 (MH⁺).

EXAMPLE 163

¹H NMR (DMSO-d₆, 65° C.) δ 2.81-2.34 (m, 2 H), 2.99 (s, 3 H), 3.28 (t,J=7.7 Hz, 2 H), 4.57 (t, J=7.4 Hz, 2 H), 5.50 (s, 2 H), 7.14-7.19 (m, 2H), 7.25-7.27 (m, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.53 (d, J=7.9 Hz, 1H), 7.63 (d, J=8.1 Hz, 1 H), 7.80-7.84 (m, 1 H), 7.91 (d, J=7.6 Hz, 1H), 7.98-8.02 (m, 1 H), 8.09 (d, J=5.0 Hz, 1 H), 8.25-8.27 (m, 1 H); MSm/e 507 (MH⁺).

EXAMPLE 164

Example 164 was prepared via synthesis of the acetate intermediateaccording to the same procedure described for Example 72 followedimmediately by deprotection of the alcohol according to the sameprocedure described for Example 73.

¹H NMR (CDCl₃) δ 1.60-1.65 (m, 2 H), 1.73-1.80 (m, 2 H), 3.64-3.70 (m, 2H), 4.33 (t, J=8.0 Hz, 2 H), 4.53-4.60 (m, 2 H), 5.44 (s, 2 H),7.24-7.37 (m, 3 H), 7.60 (d, J=5.3 Hz, 1 H), 7.77-7.81 (I, 1 H),8.35-8.38 (m, 2 H);

MS m/e 420 (MH⁺).

EXAMPLE 165

A mixture of Example 26 (100 mg, 0.27 mmol) and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's reagent, 130 mg, 0.32 mmol) in a mixture of toluene anddioxane (9:1 ratio, 10 mL) was heated in a sealed tube at 130° C. for 15hours. The solvents were removed in vacuo and the residue was suspendedin H₂O and extracted with CH₂Cl₂. The organic phase was washed withbrine, dried over MgSO₄ and evaporated. The residue was purified bypreparative TLC (5% MeOH in CH₂Cl₂), followed by trituration from Et₂Oto give 5 mg (5% yield) of Example 165 as an off white solid.

¹H NMR (DMSO-d₆) δ 1.05-1.10 (m, 2 H), 1.21-1.25 (m, 2 H), 2.07-2.15 (m,2 H), 2.67 (t, J=7.4 Hz, 2 H), 3.23-3.26 (m, 1 H), 4.49 (t, J=7.5 Hz, 2H), 5.90 (s, 2 H), 7.18 (t, J=7.5 Hz, 1 H), 7.27 (t, J=7.5Hz, 1 H), 7.53(d, J=7.9Hz, 1 H), 7.59 (d, J=5.5 Hz, 1 H), 7.63 (d, J=7.9 Hz, 1 H),8.42 (d, J=5.5 Hz, 1 H), 8.76 (s, 1 H); MS m/e 389 (MH⁺).

EXAMPLE 166

¹H NMR (CDCl₃) δ 1.00-1.07 (m, 4 H), 1.15-1.18 (m, 2 H), 1.16-1.23 (m, 2H), 2.20-2.26 (m, 2 H), 2.32-2.38 (m, 1 H), 2.96-2.30 (m, 1 H), 3.09 (t,J=7.2 Hz, 2 H), 4.53 (t, J=7.5 Hz, 2 H), 5.38 (s, 2 H), 7.18 (d, J=5.3Hz, 1 H), 7.27-7.33 (m, 2 H), 7.38-7.39 (m, 1 H), 7.77-7.79 (m, 1 H),8.34 (d, J=5.3 Hz, 1 H), 8.74 (s, 1 H); MS m/e 452 (MH⁺).

The compounds of the present invention may be administered orally,parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques),intranasally, by inhalation spray, or rectally, in dosage unitformulations containing conventional non-toxicpharmaceutically-acceptable carriers, adjuvants and vehicles.

Thus, in accordance with the present invention there is further provideda method of treating and a pharmaceutical composition for treating viralinfections such as RSV infection. The treatment involves administeringto a patient in need of such treatment a pharmaceutical compositioncomprising a pharmaceutical carrier and a therapeutically-effectiveamount of a compound of the present invention.

The pharmaceutical composition may be in the form oforally-administrable suspensions or tablets; nasal sprays, sterileinjectable preparations, for example, as sterile injectable aqueous oroleagenous suspensions or suppositories.

When administered orally as a suspension, these compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants known in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally-acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this invention can be administered orally to humans ina dosage range of 0.1 to 100 mg/kg body weight in divided doses. Onepreferred dosage range is 0.1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 0.1 to 20 mg/kg body weightorally in divided doses. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

BIOLOGICAL ACTIVITY

The antiviral activity of these compounds against respiratory syncytialvirus was determined in HEp-2 (ATCC CCL 23) cells that were seeded in 96well microtiter plates at 1.5×10⁴ cells/100 μL/well in DMEM (Dulbecco'sModified Eagle's Medium) supplemented with penicillin, streptomycin,glutamine, and 10% fetal bovine serum. The cells were incubatedovernight at 37° C., the culture medium was removed, and cells wereinfected (100 μL volume in medium containing 2% fetal bovine serum) withrespiratory syncytial virus Long strain at 5000 plaque forming units/mL.The compounds, 100 μL at appropriate dilution, were added to the cells 1hour post infection. After incubation for 4 days at 37° C., the plateswere stained with MTT solution(3-[4,5-dimethlythiazol-2-yl]-2,5-diphenyltetrazolium bromide) andincubated for 4 hours at 37° C. The media was aspirated from the cellsand 100 μL/well of acidified isopropanol (per liter: 900 mL isopropanol,100 mL Triton X100, and 4 mL conc. HCl) was added. Plates were incubatedfor 15 minutes at room temperature with shaking, and an optical density(OD 540) reading at 540 nanometer (nm) was obtained. The optical densityreading is proportional to the number of viable cells. The increase inthe number of viable cells reflects the protective, antiviral activityof the compound. Assays comparing MTT staining in uninfected cellscontaining compound with uninfected cells in the absence of compoundprovide a measure of cellular toxicity. The control compound in thisassay is Ribavirin which exhibits 100% cell protection at 2.5 μg/mL(corresponding to 10.2 μM).

The antiviral activity of compounds, designated as EC₅₀, is presented asa concentration that produces 50% cell protection in the assay. Thecompounds disclosed in this application show antiviral activity withEC₅₀'s between 50 μM and 0.001 μM. Ribavirin has an EC₅₀ of 3 μM.

What is claimed is:
 1. A compound of Formula I, and pharmaceuticallyacceptable salts thereof,

wherein: W is O or S; R₁ is -(CR′R″)_(n)-X; X is H, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, each of saidalkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionallysubstituted with one to six of the same or different halogen atoms;halogen, CN, OR′, OCOR″″, NR′R″, NR′COR″, NR′CONR″R′″, NR′SO₂R″,NR′COOR″, NR′COOR″, COR′, CR′″NNR′R″, CR′NOR″, COOR′, CONR′R″, SO_(m)R′,PO(OR′)₂, aryl, heteroaryl or non-aromatic heterocycle; m is 0-2; n is2-6; R₂ is (i) H, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, -(CH₂)_(t) C₃₋₇ cycloalkyl, -(CH₂)_(t)C₄₋₇ cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl being optionally substituted with one to six of the same ordifferent halogen atoms; SO₂R″, SO₂NR′R″ or CN; wherein t is 1-6; (ii)-(CR′R″)_(n′)-Y, wherein Y is CN, OR′,OCONR′R″, NR′R″, NCOR′, NR′SO₂R″,NR′COOR″, NR′CONR″R′″, COR′, CR′″NNR′R″, CR′NOR″, COOR′, CONR′R″,SO_(m)R′, SO₂NR′R″ or PO(OR′)₂; wherein m is -2 and n′ is 1-6; (iii)-(CR′R″)_(n″)-C₆H₄-Z, wherein the Z group may be in the ortho, meta orpara position relative to the -(CH₂)_(n″) group; Z is CN, OR′, OCONR′R″,NO₂, NCOR′, NR′SO₂R″, NR′COOR″, NR′CONR″R′″, COR′, CR′″NNR′R″, CR′NOR″,COOR′, CONR′R″, SO_(m)R′, SO₂NR′R″ or PO(OR′)₂; m is 0-2; n″ is 0-6; or(iv) -(CR′R″)N′″-heteroaryl, wherein n′″ is 0-6; (v)-(CR′R″)_(n′″)-non-aromatic heterocycle, wherein n_(40 ″ is) 0-6; R₃,R₄, R₅ and R₆ are each independently hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆alkyl substituted with one to six of the same or different halogenatoms, OR′, CN, COR′, COOR′, CON′R″, or NO₂; A, B, E, D are eachindependently C—H, C—Q—, N, or N—O; provided only one of A, B, E or D isnot C—H or C—Q; wherein Q is halogen, C₁₋₃ alkyl or C₁₋₃ alkylsubstituted with one to three of the same or different halogen atoms;R′, R″, R′″ are each independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, each of said alkyl,alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionallysubstituted with one to six of the same or different halogen atoms; orR′ and R″ taken together form a cyclic alkyl group having 3 to 7 carbonatoms; benzyl, or aryl; R″″ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, NR′R″, CR′NR″R′″, aryl, heteroaryl,non-aromatic hetercycle; and Non-aromatic heterocycle is a 3-7 memberednon-aromatic ring containing at least one and up to 4 non-carbon atomsselected from the group consisting of O, S, N, and NR′; Aryl is phenyl,naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; Heteroaryl is a4-7 membered aromatic ring which contains one to five heteroatomsindependently selected from the group consisting of O, S, N and NR′,wherein sadi aromatic ring is optionally fused to group B′; B′ is anaromatic group selected from the group consisting of phenyl, 1-naphthyl,2-naphthyl, idenyl, azulenyl, flurenyl, and anthracenyl; Aryl, B′, said4-7 membered aromatic ring, and said 3-7 membered non-aromatic ring mayeach independently contain one to five substituents which are eachindependently selected from R₇, R₈, R₉, R₁₀ or R₁₁; and R₇, R₈, R₉, R₁₀and R₁₁ are each independently (i) H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, each of said alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, being optionally substitutedwith one to six of the same or different halogen atoms; and (ii)halogen, CN, NO₂, OR′, NR′R″, COR′, COOR′, CONR′R″, OCOR′, NR′COR″,SO_(m)R′, SO₂NR′R″, PO(OR′)_(2.)
 2. The compound of claim 1 whereinheteroaryl is selected from the group consisting of 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazol-5-one,1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzoylfuranyl, benzo[b]thiophenyl,1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, tetrazole and phenoxazinyl.
 3. A compound ofclaim 2 wherein: R₁ is —(CH₂)_(n)—X; X is H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, each of said alkyl,alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionallysubstituted with one to six of the same or different halogen atoms;halogen, CN, OR′, OCOR″″, NR′R″, NR′COR″, NR′COOR″, COR′, CR′″NNR′R′R″,CR′NOR″, COOR′, CONR′R″, SO_(m)R′, aryl or heteroaryl; m is 0-2; n is2-4; R₂ is (i) H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C3-6 cycloalkenyl, —(CH₂)_(t) C₃₋₇ cycloalkyl, —(CH₂)_(t)C₄₋₇ cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl being optionally substituted with one to six of the same ordifferent halogen atoms; SO₂R″, SO₂NR′R″ or CN; wherein t is 1-6; (ii)—(CH₂)_(n′)—Y, wherein Y is CN, OR′, COR′, COOR′, CONR′R″, SO_(m)R′,SO₂NR!R″, PO(OR′)₂ wherein m is 0-2 and n′ is 1-6; or (iii)—(CH₂)n″—C₆H₄—Z, wherein the Z group may be in the ortho, meta or paraposition relative to the —(CH₂)n″ group; Z is CN, OR′, COR′ or SO_(m)R′;m is 0-2; n″ is 0-3; R₃, R₄, R₅, and R₆ are each independently hydrogen,halogen, C I₆ alkyl, optionally substituted with one to six of the sameor different halogen atoms; and A, B, E, D are each independently C—H orN; provided at least one of A, B, E or D is not C—H.
 4. A compound ofclaim 2 wherein: R₃, R₄, R₅ and R₆ are each H; A, B and D are each C—H;and E is N.
 5. A compound of claim 2 wherein: R₃, R₄, R₅ and R₆ are eachH; A, B and D are each C—H; and E is N.
 6. A pharmaceutical compositionwhich comprises a therapeutically effective amount of an anti-RSVcompound having Formula I, and pharmaceutically acceptable saltsthereof, as claimed in any one of claims 1-5, and a pharmaceuticallyacceptable carrier.
 7. A method for treating mammals infected with RSV,and in need thereof, which comprises administering to said mammal atherapeutically effective amount of a compound having the Formula I, andpharmaceutically acceptable salts thereof, as claimed in any one ofclaims 1-5.